Acyl Radical Chemistry Via Visible-Light Photoredox Catalysis

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2019, 51, 303–333 review 303 en

Syn thesis A. Banerjee et al. Review

Acyl Radical Chemistry via Visible-Light Photoredox Catalysis

Arghya Banerjee‡a Zhen Lei‡a Ming-Yu Ngai*a,b a Department of Chemistry, Stony Brook University, Stony Brook, New York, 11794-3400, USA b Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York, 11794-3400, USA

‡ These authors contributed equally to this work.

Received: 31.08.2018 subsequent carbonylation by CO (Scheme 1, method A). The Accepted after revision: 19.10.2018 use of acyl selenides in the presence of an organotin re- Published online: 12.12.2018 4a,6 DOI: 10.1055/s-0037-1610329; Art ID: ss-2018-e0584-r agent such as Bu3SnH together with a radical initiator is an alternative means of generating acyl radicals (method Abstract Visible-light photoredox catalysis enables easy access to acyl B). Through the photochemical cleavage of the RC(O)–X radicals under mild reaction conditions. Reactive acyl radicals, generat- bond of acyl tellurides (X = Te–R′),7 benzoylphosphine ox- ed from various acyl precursors such as aldehydes, α-keto acids, carbox- 8 ylic acids, anhydrides, acyl thioesters, acyl chlorides, or acyl silanes, can ides [X = P(O)Ph2] can also afford acyl radicals. α-Hydroxy undergo a diverse range of synthetically useful transformations, which or α-amino ketones RC(O)–X [X = CH(OH)R or were previously difficult or inaccessible. This review summarizes the re- 8a,b,9 CH(NH2)R], cyclic ketones (via a Norrish type I cleav- cent progress on visible-light-driven acyl radical generation using tran- age),10 esters (via photo-Fries rearrangements),11 or acyl- sition-metal photoredox catalysts, metallaphotocatalysts, hypervalent 12 iodine catalysts or organic photocatalysts. cobalt salophen reagents [X = Co(salophen)Py] can all also 1 Introduction deliver acyl radicals (method C). In addition, peroxide-me- 2 The Scope of This Review diated homolytic abstraction of a hydrogen atom from alde- 3 Aldehydes as a Source of Acyl Radicals hydes and α-keto acids is a viable option for the generation 4 α-Keto Acids as a Source of Acyl Radicals of an acyl radical13 (method D). Many directed or non-di- 5 Carboxylic Acids as a Source of Acyl Radicals 6 Anhydrides as a Source of Acyl Radicals rected C–H acylation processes catalyzed by transition met- 7 Acyl Thioesters as a Source of Acyl Radicals als have been developed in the last decades using this strat- 8 Acyl Chlorides as a Source of Acyl Radicals egy.14 However, from a synthetic viewpoint, their utility 9 Acyl Silanes as a Source of Acyl Radicals was somewhat limited due to the requirement of high ener- 10 Conclusions and Future Outlook gy conditions such as high temperatures, UV irradiation, or Key words acylation, photoredox catalysis, acyl radicals, visible light, stoichiometric amounts of toxic reagents or oxidants.

single-electron transfer, oxidation, reduction, cross-coupling This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. CO Method A: R

O Radical initiator 1 Introduction Method B: R SeR1 O

R O hv 1 Method C: Acyl radicals are nucleophilic in nature and serve as R X X = TeR, COR, POR2, CH(OH)R, CH(NH2)R, Co(salophen)Py versatile synthetic intermediates in Giese-type additions to O Peroxide 2 Method D: activated alkenes, Minisci-type acylations of het- R Y Y = H, COOH eroarenes,3 and for the preparation of a wide range of natu- Scheme 1 Traditional methods of acyl radical generation5–13 ral and biologically active molecules.4 Conventional ap- proaches to the generation of acyl radicals, however, gener- ally require harsh reaction conditions such as UV Recently, visible-light photoredox catalysis has emerged irradiation or high temperatures.5 One way to access these as a powerful tool for the synthesis of organic scaffolds that intermediates is by generation of alkyl radicals from alkyl are difficult to prepare by traditional methods.15 Upon exci- iodides through photochemical or thermal initiation and tation with visible light, photoredox catalysts (PC) generate

Syn thesis A. Banerjee et al. Review an excited photocatalyst (*PC) which can act by single-elec- in such visible-light-driven acyl radical generation using al- tron transfer (SET) processes, not only as a one-electron ox- dehydes, α-ketocarboxylic acids, carboxylic acids, carboxyl- idant or a one-electron reductant but also as an energy do- ic acid anhydrides, acyl thioesters, acid chlorides, or acyl nor, activating acceptor molecules by an energy-transfer silanes as acyl radical precursors (Scheme 2). The scope, (EnT) process.16 This photoredox strategy, therefore, pro- limitations, and the proposed reaction mechanism of each vides a new platform for radical reactions by obviating the transformation are discussed. It is noteworthy that most of need for radical initiators and a stoichiometric amount of the reactions described in this review proceed through strong reducing agents. All these features make photoredox photoredox catalytic cycles, but the radical chain mecha- catalysis a sustainable alternative from the viewpoint of nism cannot be excluded. radical reactions and one that can be utilized as an elegant method to access acyl radicals. O O R H O

R Cl R SiMe3 2 The Scope of This Review O

O R O R1 OH Over the past decade, various research groups have re- R S R ported the visible-light-mediated generation of acyl radi- O cals using photoredox catalysts, metallaphotocatalysts, hy- O O O pervalent iodine photocatalysts, or organic photocatalysts. R O R R OH This review aims to provide an overview of recent progress Scheme 2 Various modes of acyl radical generation by visible-light photocatalysis

Biographical Sketches

Arghya Banerjee was born in wahati, India in 2010, he under- under the supervision of Prof. West Bengal, India. He obtained took his Ph.D. at the same Ming-Yu Ngai. His current re- his B.Sc. degree in chemistry institute under the guidance of search is focused on the devel- from Ramakrishna Mission Vidy- Prof. Bhisma K. Patel. In 2017, opment of novel acylation amandira, Belur in 2008. After he joined Stony Brook Universi- strategies using photoredox ca- completing his M.Sc. at IIT Gu- ty as a postdoctoral associate talysis.

Zhen Lei was born in Xi’an, with Prof. Susan L. Bane on bo- Ming-Yu Ngai. His current re- China. In 2011, he graduated razine-containing bioorthogo- search focuses on the develop- with a B.Sc. degree in chemistry nal reactions and was awarded ment of photoredox-catalyzed from Sichuan University, China. his M.Sc. degree in 2015. In the C–H functionalization and

He continued his studies at the same year, he began his Ph.D. asymmetric reactions. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. State University of New York at studies at Stony Brook Universi- Binghamton, where he worked ty under the guidance of Prof.

Ming-Yu Ngai was born in Prof. Michael J. Krische in 2008, he was appointed as an assis- Fuching, China and graduated he worked with Prof. Barry M. tant professor at the Depart- with a B.Sc. degree from the Trost at Stanford University as a ment of Chemistry at Stony University of Hong Kong in Croucher postdoctoral fellow Brook University. His research 2003. After receiving his Ph.D. (2009–2011) and then with focuses on the development of degree with honors in chemis- Prof. Tobias Ritter at Harvard photoredox catalysis and fluo- try from the University of Texas University as a postdoctoral as- rine chemistry. at Austin under the guidance of sociate (2011–2013). In 2013,

Syn thesis A. Banerjee et al. Review

3 Aldehydes as a Source of Acyl Radicals agent that abstracts an aldehyde hydrogen atom to form an acyl radical 5.2 and a hydroperoxyl radical (5.3). These two Aldehydes are abundant, readily available, and versatile radicals recombine to give a peroxy acid 5.4, which reacts intermediates that are commonly converted into acyl radi- with another molecule of the aldehyde to afford an adduct cals through hydrogen atom transfer (HAT). In this process, 5.5. This compound then undergoes a Baeyer–Villiger-type a radical species generated from a HAT reagent abstracts rearrangement to form the desired carboxylic acid product the hydrogen atom of aldehydes forming an acyl radical. 5.6 (Scheme 5). Common HAT reagents4b,17 such as persulfates18 and tert- O O O 19 OH butyl hydroperoxide, which are used in traditional ther- HAT + O OH R H R R O mal radical chemistry, are also applicable to photoredox ca- 5.11 3 5.2 5.3 5.4 O2 O2 talysis. Compounds such as quinuclidine20 and Eosin Y21 O R H have also emerged as new HAT reagents for activation of al- EnT H O O O H dehydes. The bond dissociation energies (BDEs) of the C–H R *Ir(dFppy)3 Ir(dFppy)3 R OH R O O of different aldehydes are strikingly similar within 88.0 5.6 5.5 kcal/mol to 89.4 kcal/mol, while the BDEs of common HAT reagents can range from 88.2 kcal/mol to 106.3 kcal/mol Scheme 5 Proposed mechanism for aerobic oxidation of aldehydes to acyl radicals via photoinduced energy transfer. Adapted with permission (Scheme 3).20,22 from ref 23. Copyright (2013) Elsevier Ltd

C–H BDE of substrates O O O O O O Me In 2014, Zeng et al. published a photoredox catalysis H H H H F3C H H Me H (ref 22c) (ref 22h) (ref 22b) (ref 22j) (ref 22h) (ref 22c) method to generate benzoyl radicals from benzaldehydes 88.0 88.7 88.7 89.0 89.1 89.4 for the acylation of phenanthridine (Scheme 6).25 Although various benzaldehydes with halogen, alkyl, methoxy, and 88.0 89.0 90.0 100.0 105.0 (kcal/mol) acetoxy substituents could serve as benzoyl radical donors, 88.2 88.2 90.4 100 105 106.3 phenanthridine was the only radical acceptor reported in (ref 22a) (ref 22j) (ref 22e) (ref 20) (ref 22d) (ref 22i) HO H O H O O O this work. The reaction afforded the desired products in O O H H H N O yields ranging from 27–73%, but aldehydes with strong H electron-donating groups such as p-NMe2 or strong elec- X–H BDE of reagents tron-withdrawing groups such as p-NO2 failed to afford the Scheme 3 Selected bond dissociation energies (BDEs) of common al- desired products. dehydes and HAT reagents O O N fac-Ir(ppy) (1.00 mol%) N H 3 (NH4)2S2O8 (2.00 equiv) R In 2013, Cho et al. reported a synthesis of carboxylic ac- R + ids through photocatalytic oxidation of aldehydes using DMSO (0.125 M) 4.00 equiv 1.00 equiv 25 W CFL, 48 h 23 CFL = compact fluorescent light molecular O2 as an oxidant and a HAT reagent (Scheme 4). R = halogen, Me, aryl, AcO, MeO Both electron-deficient and electron-rich aromatic alde- O Cl O AcO O O N N N N hydes, as well as aliphatic aldehydes, were oxidized to carboxylic acids in excellent yields (90–99%).

58% 40% 27% 51% O O fac-Ir(dFppy)3 (0.500–1.00 mol%) R H R OH 25 O2, MeCN (0.250 M), r.t. Scheme 6 Photocatalytic aroylation of phenanthridine R = Aryl, akyl blue LEDs, 3–12 h This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

O O O O F C The proposed mechanism of this reaction is shown in OH 3 OH OH OH 6 red 26 Scheme 7. The persulfate salt 7.1 (E1/2 = +0.35 V vs SCE) MeO IV/*III oxidizes the excited fac-*Ir(ppy)3 (E1/2 = –1.73 V vs SCE) 99% 92% 96% 90% via single-electron transfer (SET) to form a sulfate ion 7.3 Scheme 4 Formation of carboxylic acids via photoinduced energy and a sulfate radical anion 7.2. The resulting sulfate radical transfer23 anion abstracts a benzaldehyde hydrogen atom via a HAT process to give the benzoyl radical 7.5. Subsequent addition T It was proposed that the excited *Ir(dFppy)3 (E = 60.1 of the benzoyl radical to phenanthridine generates an 24 T 2– kcal/mol) (E = triplet state energy of the excited photo- amidyl radical 7.8, which is deprotonated by SO4 to afford 3 1 catalyst) converts triplet O2 into singlet O2 via photoin- a radical anion 7.9. This radical anion is then oxidized by 1 IV duced energy transfer. Singlet O2 then serves as a HAT re- the Ir (ppy)3 to form the final product 7.10.

Syn thesis A. Banerjee et al. Review

2– Wang and Li proposed that the t-butyl hydroperoxide S2O8 SO4 HSO4 7.1 7.2 7.6 SET serves two roles in the reaction. First, TBHP oxidizes the ex- II III/*II III SO 2– cited *Ru (E = –0.81 V vs SCE) to form a hydroxide and *Ir (ppy)3 4 O O 1/2 7.3 t • H N a t-butoxy radical BuO , which subsequently abstracts a hydrogen atom from the aldehyde to give a benzoyl radical. IrIV(ppy) 7.4 7.5 3 Second, deprotonation of the TBHP by the hydroxide ion IrIII(ppy) 3 7.7 – t – SET 7.6 OH gives a t-butyl peroxide anion BuOO , which reduces O O O HSO4 III 2-+ N N N the oxidized Ru (bpy)3 regenerating the photocatalyst and forming a t-butyl peroxy radical tBuOO•. Recombination SO 2– 4 of the t-butyl peroxy radical with the radical intermediate 7.9 7.3 7.8 7.10 10.7 affords a β-peroxy ketone 10.8, which undergoes base- Scheme 7 A persulfate salt as the HAT reagent under photocatalytic promoted elimination of tBuO– to produce the final product conditions. Adapted with permission from ref 25. Copyright (2014) Elsevier Ltd 10.9 (Scheme 10).

H t-Butyl hydroperoxide (TBHP) is a versatile HAT reagent. tBuOH 10.4 t O *RuII(bpy) 2+ BuOOH 10.3 While single-electron reduction of TBHP generates the t- 3 10.1 – butoxy radical, single-electron oxidation of deprotonated SET OH 10.5 TBHP affords the t-butyl peroxy radical (Scheme 8). Both of tBuO these radical species efficiently abstract an aldehyde hydro- 10.2 27 II 2+ III 3+ gen atom, giving an acyl radical. Consequently, combining Ru (bpy)3 Ru (bpy)3 Cl 10.6 OtBu TBHP with photoredox catalysis provides a useful and mild O O SET tool for the formation of acyl radicals from aldehydes. O H 10.10 tBuOO– tBuOO Cl 10.8 – 10.11 10.7 Cl O reduction O OH a OH Cs2CO3 SET tBuOOH O O 10.1 HAT tBuOH R H R O O – oxidation O O b O O SET 10.9 Cl Scheme 8 Abstraction of an aldehyde hydrogen using TBHP Scheme 10 Proposed mechanism for the photocatalytic synthesis of α,β-epoxy ketones via an acyl radical intermediate. Adapted with per- In 2015, Wang and Li reported a synthesis of α,β-epoxy mission from ref 28. [Copyright (2015) American Chemical Society] ketones from styrenes and benzaldehydes under photocatalytic conditions using TBHP as a HAT reagent.28 Aromatic aldehydes with halogen, alkyl, and methoxy substituents and In 2017, Hong et al. reported an intramolecular cycliza- thiophenecarboxaldehyde reacted well, giving 61–83% tion and epoxidation (Scheme 11), developed in analogy to yields (Scheme 9). In terms of the styrene scope, arenes the intermolecular method reported by Wang and Li,28 us- with halogen, alkyl, and methoxy substituents, pyridine, ing TBHP as the HAT reagent.29 The reaction conditions naphthalene, and 1,1-disubstituted styrenes including 1,1- were applicable to both allyloxy and allylamino substrates diphenylethylene and α-methylstyrene underwent cou- When X = O pling to afford the desired products in 51–85% yields. 1 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O O R2 R = halogen, OMe, alkyl, Ru(bpy)3Cl2 (1.00 mol%) CO2Me, arene TBHP (5.00 equiv) 2 1 H 1 R = Me, Et O R3 Ru(bpy) Cl (2.00 mol%) R R O 3 2 O R3 K2CO3 (3.00 equiv) TBHP (4.00 equiv) O 2 X R iPrOAc (0.100 M) X When X = NTs, NBoc 1 H 2 Cs2CO3 (2.00 equiv) 1 2 R R R1 R2 Blue LED, 20–24 h R = R = H + X 4 Å MS (2.00 wt%), MeCN (0.0500 M) X 4.00 equiv 1.00 equiv 45 W house bulb, r.t., 36 h O O O Me O Me MeO C X = CH or N; R1, R2 = halogens, alkyl, OMe; R3 = H, Me, Ph 2 O O O O O Me O OMe O O O O O O O O O O S 73% (48%) 64% (47%) 60% (42%) 48% (33%) O O O Cl Cl Cl Cl O 82% 65% 62% 83% O I O O O Me O O O O N N O O O O Ph O O Ts Boc 56% 59% 73% 64% N 85% 58% 63% 64% Scheme 11 Intramolecular acyl radical addition/epoxidation.29 The Scheme 9 Photocatalytic synthesis of α,β-epoxy ketones via acyl radi- yields in parentheses were obtained by the reaction of benzyl alcohol cal addition using TBHP28 substrates using 8 equivalents of TBHP

Syn thesis A. Banerjee et al. Review to produce the desired spiroepoxy chroman-4-ones and Following Wang’s discovery using TBHP for the genera- enaminones. Interestingly, a three-step tandem process tion of acyl radicals, Cho and Iqbal, in 2016, disclosed a starting from benzyl alcohol and using 8 equivalents of photocatalytic amide formation protocol from aldehydes TBHP also occurred, albeit with lower yields being ob- and amines (Scheme 13).30 It was proposed that reduction tained. of TBHP affords hydroxide and the t-butoxy radical, which It was reported that addition of TEMPO completely in- undergoes HAT with benzaldehyde to form the benzoyl rad- hibits the reaction and forms the TEMPO adduct, which in- ical 13.5 (path a). This radical abstracts the chlorine atom dicates the involvement of a radical intermediate. Exposure from N-chlorosuccinimide, forming benzoyl chloride 13.8, i of the β-peroxy ketone 12.10 to a solution of K2CO3 in P- which reacts with an amine to afford the amide product. rOAc afforded the desired α-carbonyl epoxide 12.11, sug- The reaction proceeds with a sub-stoichiometric quantity gesting that the product is derived from the β-peroxy ke- of TBHP, leading to speculation that other radical species tone intermediate. Based on these experimental results and such as the t-butyl peroxy radical (path b) and the succin- the observation that benzylic alcohols also afforded the de- imide radical (path c) generated in the reaction mixture sired spiroepoxy chroman-4-ones, tandem oxidation of the might also be responsible for the HAT of benzaldehyde lead- benzylic alcohols to aldehydes followed by radical cycliza- ing to the benzoyl radical. tion was proposed (Scheme 12). TBHP (12.1) oxidatively This reaction has a broad substrate scope. Both elec- II 2+ III 3+ quenches the excited *Ru (bpy)3 to generate Ru (bpy)3 tron-rich and electron-poor benzaldehydes with substitu- t • and a t-butoxy radical ( BuO ) (12.2). This radical abstracts ents such as alkyl, halogens, cyano, and CF3 underwent cou- an α-hydrogen atom from the benzylic alcohol 12.3 to gen- pling to afford the desired amides in 65–87% yields. Primary erate an α-hydroxy radical 12.5, which is oxidized and and secondary amines, anilines, and aminopyridines were deprotonated to form benzaldehyde 12.7. Once the benzal- all viable substrates giving the desired products in 58–82% dehyde is formed, the rest of the reaction mechanism is yields. This strategy was used in the synthesis of the anti- parallel to the catalytic cycle proposed by Wang and Li.28 depressant moclobemide 6 and the D3 receptor GR103691 intermediate (Scheme 13). Benzylic alcohol cycle

Ru(bpy) Cl (2.00 mol%) OH t O 3 2 O 2 3 O BuOH TBHP (1.30 equiv) NHR R H 12.4 R3 t II 2+ 1 H NCS (3.00 equiv) 1 Cl (1.50 equiv) N H BuOOH *Ru (bpy)3 R R 1 R 2 O 12.1 MeCN (0.250 M) R 7 W blue light, r.t., 24 h 1.00 equiv – OH SET 12.3 1 2 3 + R = halogen, alkyl, CN, CF3; R = Bn, Ph, pyridinyl, alkyl; R = H, alkyl tBuO O 12.2

III 3+ II 2+ H Ru (bpy)3 Ru (bpy)3 O t t BuOH 13.4 OH SET OH *RuII(bpy) 2+ BuOOH HN + 3 13.1 13.3

H H – path a O SET OH path c + 13.7 O – O O OH tBuO 12.5 12.6 13.2 N

O RuII(bpy) 2+ RuIII(bpy) 3+ O H2O 3 3 13.6 Benzaldehyde cycle H O O SET O Cl t path b tBuOH BuOO 12.7 t – 13.10 O 12.4 13.9 BuOO t 13.5 13.8 *RuII(bpy) 2+ BuOOH O 3 12.1 –OH HAT Cl N t H This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. SET –OH BuOOH O 13.1 + O 13.6 NCS tBuO 12.2 O O O O II 2+ III 3+ O N Ru (bpy)3 Ru (bpy)3 NHBn NHBn N N 12.8 H H Br Br OtBu Me NC SET O O 70% 79% 70% 70% O Me 12.12 tBuOO– tBuOO O O O O N N Me N N OMe – 12.13 12.10 OH O K CO t N N N 2 3 – O Bu H H H 12.9 iPrOAc tBuOOH Cl Br O moclobemide 6 D3 receptor GR103691 intermediate O 70% 77% 65% Scheme 13 Photocatalytic amide synthesis from benzaldehydes using 12.11 TBHP30 Scheme 12 Photocatalytic cycle involving benzaldehyde and benzylic alcohol29

Syn thesis A. Banerjee et al. Review

In 2017, Glorius et al. reported a photocatalytic alky- – nylation of aldehydes, formates, and formamides using OAc only quencher alkynylbenziodoxolones as the alkyne source and the re- I O– sulting benziodoxolonyl radical as a HAT reagent.31 This re- HOAc O 15.1 action has a broad substrate scope and a wide range of al- *IrIII I kyl, vinyl, aryl, and heteroaryl aldehydes, formates, and for- OH mamides reacted with various aryl or silyl SET O IrIII 15.3 I alkynylbenziodoxolones to afford the desired alkynylated I O HAT O products in 46–90% yields (Scheme 14). The carbonyl radi- O– H O cals generated under the optimized conditions failed to re- 15.2 O IrII SET act with double bonds, and thus the method is compatible 15.4 15.1 with α,β-unsaturated aldehydes. This transformation is also I O compatible with late-stage alkynylation of complex sub- O O O O strates such as cholesterol, lithocholic acid, probenecid, and 15.7 TEMPO TEMPO adapalene derivatives, giving the desired products in 48– Ph TEMPO adduct 15.8 78% yields. 15.5

I R2 O

O 15.6 O O [Ir(dF(CF3)ppy)2(5,5'-dCF3bpy)]PF6 (2.00 mol%) I sodium 2-iodobenzoate (10.0 mol%) R1 1 + Scheme 15 Proposed mechanism for the photocatalytic alkynylation R H O R2 BIOAc (30.0 mol%), DCE (0.400 M) 31 blue LED, r.t., 24 to 48 h of aldehydes O 1.50 equiv 1.00 equiv R1 = alkyl, vinyl, amine, aniline, PhO, PrO, arene and heteroarene; R2 = arene, triisopropylsilyl In 2017, MacMillan et al. reported a triple catalytic pro- O O O O tocol for arylation, vinylation, and alkylation of aldehydes S

Ph Ph Ph Ph via an acyl radical intermediate using aryl, vinyl, and alkyl 85% 80% 70% 75% bromides as coupling partners and quinuclidine, NiII, and a O O O 33 O photocatalyst as catalysts (Scheme 16). This approach has O N O TIPS a very broad scope and is insensitive to the electronic na- TIPS 67% F 51%a 46%a 65%a ture of the aryl bromides. Heteroaryl, cyclic and acyclic vi- O O O nyl, and alkyl bromides are viable substrates and afforded Me O O the desired ketones in 50–90% yields. Regarding the alde- Me TIPS TIPS O hyde scope, both alkyl and aryl aldehydes coupled well to Me H afford the desired products in 70–90% yields, although 6–10 H H lithocholic acid derivative MeO adapalene derivative AcO 72% ADM 48% equivalents of aryl aldehydes were needed.

a Scheme 14 Photocatalytic alkynylation of aldehydes. Reaction time = O [Ir(dF(CF3)ppy)2(5,5'-dCF3bpy)]PF6 (1.00 mol%) O NiBr ⋅dtbbpy (10.0 mol%) 31 Br 2 48 h. BI = benziodoxolonyl group, ADM = adamantan-1-yl R1 H R2 R1 R2 quinuclidine (10.0 mol%), K2CO3 (2.00 equiv) 2.00 equiv 1.00 equiv 1,4-dioxane, r.t., 20 h, 34 W blue LED R1 = alkyl, or aryl; R2 = alkyl, vinyl, aryl, or heteroaryl

Stern–Volmer quenching experiments showed that the O Me Me O O O HO

2-iodobenzoate was the only component that quenched the Me 3 BocN photocatalyst. In the presence of TEMPO, the formation of CF3 N CF3 N CF3 F N CF3 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the alkynylated product was completely inhibited, and a 88% 87% 81% 81%b O O Me O O TEMPO-trapped adduct was obtained. On the basis of these CN CN Me results, the authors proposed that 2-iodobenzoate (15.1) BocN BocN BocN BocN O N reductively quenches the excited [*Ir(dF(CF3)ppy)2(5,5′- 78% 72%a 55% 56% III*/II 32 II dCF3bpy)]PF6 (E1/2 = +1.21 V vs SCE) to form Ir and the Scheme 16 Alkylation, vinylation, and arylation of aldehydes via triple a b 33 2-iodobenzoyloxyl radical 15.2 (Scheme 15). Hydrogen- catalysis. K2CO3 (2.00 equiv). p-fluorobenzaldehyde (10.0 equiv) atom abstraction of the aldehyde hydrogen by 15.2 provides a carbonyl radical 15.5 that reacts with alkynylbenziodox- olone 15.6 to form the desired product 15.8, simultaneous- The mechanistic hypothesis for this triple catalysis is ox ly releasing the benziodoxolonyl radical 15.7. Reduction of shown in Scheme 17. SET from quinuclidine (E1/2 = +1.10 V II 20 15.7 with Ir forms 15.1 and regenerates the ground state Ir vs SCE in MeCN) to the excited [*Ir(dF(CF3)ppy)2(5,5′- III*/II photocatalyst. Alternatively, since 15.7 is in equilibrium dCF3bpy)]PF6 (E1/2 = +1.21 V vs SCE) generates an elec- with 15.2, it can undergo a HAT reaction directly. trophilic quinuclidinium cation radical 17.2, which selectively abstracts the weak and hydridic aldehyde hydrogen

Syn thesis A. Banerjee et al. Review atom to form the acyl radical 17.5. The α-amino C–H bond the aldehyde hydridic hydrogen to form an acyl radical. The also exhibits hydridic bond polarization and is subjected to acyl radical is then intercepted by an olefin to give the car- hydrogen atom abstraction.34 The authors discovered that bon radical intermediate 19.7. A single-electron transfer the reaction performed in 1,4-dioxane circumvented the from IrII to this intermediate, followed by protonation, de- unwanted competing α-amino C–H activation affording ex- livers the desired product and regenerates the IrIII catalyst clusively the desired acylated product, whereas MeCN or (Scheme 19). DMSO solvents delivered the α-amino arylation product in O addition to the desired product. Oxidative addition of the O O aryl bromide to Ni0 on the other hand delivers an aryl-NiII H O 19.6 O species 17.7, which is intercepted by the acyl radical 17.5 to 19.4 III HAT form acyl-Ni complex 17.8. Subsequently, reductive elimi- 19.5 19.7 nation forms the desired ketone product and a NiI species II I N 17.9. A single-electron transfer between Ir and Ni regener- N 19.2 III 0 + ates the Ir and Ni catalysts and completes the catalytic H IrII 19.3 cycle. SET + + – H SET + H N O O O 19.1

–H+ Br Br N N Boc 19.8 L NiII Ar III H + n 17.5 *IrIII Ir 17.6 17.7 O 17.3 Br N III Ln Ni Ar 0 Scheme 19 Photocatalytic hydroacylation of alkenes promoted by qui- N 17.1 LnNi 17.8 Boc IrII O Alk nuclidine35 17.5 HAT SET SET –Br N L NiI Br O O n 17.9 35 17.2 H In the same paper, Liu et al. presented their prelimi- N N Boc Boc 17.10 nary results of a catalytic cross-coupling process using the 17.4 *IrIII IrIII Ir photocatalyst and NiCl2. In contrast to MacMillan’s work,33 Liu et al. used a stoichiometric amount of quinucli- Scheme 17 Proposed reaction mechanism for the triple catalysis. dine, and the scope of the reaction was significantly limited Adapted with permission from ref 33. Copyright (2017) American as a result of the unwanted reduction of aryl bromides Chemical Society (Scheme 20).

[Ir(dF(CF3)ppy)2(5,5'-dCF3bpy)]PF6 (1.00 mol%) O Br Also in 2017, Liu et al. used the quinuclidine catalyst to O NiCl2·DME(1.00 mol%), dtbbpy (1.20 mol%) R2 R1 generate the acyl radical from aldehydes under photoredox R1 H + quinuclidine (1.20 equiv), DMSO (0.100 M) R2 r.t., 24 h, 34 W blue LED conditions (Scheme 18).35 Both aromatic and aliphatic alde- 5.00 equiv 1.00 equiv R1 = alkyl, arenes; R2 = H, CN, Ac hydes were viable substrates under the dual-catalytic con- O O O Me O Me ditions. The synthetic utility was also well demonstrated by Me a variety of electron-deficient olefin acceptors. Ac Ac Ac NC With a mechanism similar to that described in Scheme 60% 36% 49% 50% III 17, reductive quenching of the excited *Ir catalyst by qui- Scheme 20 Preliminary results of metallophotocatalytic cross-cou- 35 nuclidine (19.1) forms a HAT reagent 19.2, which abstracts pling using NiCl2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

t R4 4 In 2018, Itoh et al. used 2-t-butylanthraquinone (2- Bu- O [Ir(dF(CF )ppy) (5,5'-dCF bpy)]PF (1.00 mol%) O R R2 3 2 3 6 EWG 1 AQN) as a photocatalyst and benzoyl peroxide (BPO) as an 1 quinuclidine (10.0 mol%), MeCN (0.300 M) R 2 EWG R H 3 R R r.t., 12 h, 34 W blue LED R3 5.00 equiv 1.00 equiv oxidant in the presence of potassium carbonate to synthe- 1 2 3 4 36 R = aryl, alkyl; R , R , R = H, alkyl, CO2Me; EWG = ketone, CO2Me, SO2Ph, CN size 3-acyl-4-arylcoumarin derivatives (Scheme 21). Al-

O O Me O kyl, alkoxy, and acetoxy groups on both the benzaldehyde

COOMe COOMe SO2Ph and propynate substrates were well tolerated. The authors COOMe COOMe showed that many of their coumarin products had potential 60% 81% 71% O Me O O biological applications as demonstrated by their effective- O COOMe CN ness in the inhibition of PSA secretion and the proliferation of androgen-dependent prostate cancer. 70% 99% 38% The proposed mechanism for this reaction is depicted in Scheme 18 Photocatalytic hydroacylation using quinuclidine as the Scheme 22. Photoexcited 2-t-butylanthraquinone 22.2 acts 35 HAT reagent as a HAT reagent and abstracts the formyl hydrogen atom of

Syn thesis A. Banerjee et al. Review

O Ph t In 2018, Wu et al. reported that excited Eosin Y, func- 2- Bu-AQN (10.0 mol%) O Ph BPO (200 mol%) 1 H tioning as a HAT reagent, can abstract the aldehyde hydro- R 2 K2CO3 (50.0 mol%) R R1 R2 tamyl alcohol, 20 h gen atom under irradiation with an 18 W white LED light O O O O Ar, visible light 21 10.0 equiv 1.00 equiv (Scheme 23). Alkyl, aryl and heteroaryl aldehydes reacted 1 2 R = alkyl, MeO, halogen, CF3, Ph; R = alkyl, MeO, halogen, AcO, Ac, MeO2C with electron-deficient 1,1-dicyano-2-phenylethylene to O Ph O Ph O Ph afford the desired products in 83–94% yields. Benzaldehyde O Ph can react with a SOMOphile such as methyl 2-[(phenylsul- O Me O O F O O fonyl)methyl]acrylate to form an allylation product in 48% F3C O O 71% 74% 66% 58% yield. It should be noted that the major focus of Wu’s work

O Ph O Ph O Ph was on the alkylation of a wide range of C–H bonds with OMe electron-deficient alkenes under photocatalytic conditions.

Me O O Me Me O O OMe Me O O The C–H partners include THF, thioethers, amides, alcohols, 70% 58% 50% and cyclohexane. However, these coupling reactions are outside the scope of this review. Scheme 21 Photocatalytic formation of 3-acyl-4-arylcoumarin derivatives catalyzed by anthraquinone derivatives36 O CN CO2Me Eosin Y (2.00 mol%) O CN O CO2Me acetone (0.200 M) + or SO2Ph or R1 H CN R1 CN R1 50–60 °C, 24–48 h Ph 18 W white LED strip Ph benzaldehyde, forming the semiquinone radical37 AQH• 5.00 equiv 1.00 equiv 1.00 equiv R1 = alkyl, aryl, heteroaryl (22.3) and the benzoyl radical 22.5. Addition of the benzoyl O CN O CN O CN H O CN O CO2Me radical to the propynate 22.6 generates a vinyl radical inter- S N pentyl CN Ph CN CN CN Ph mediate 22.7, which undergoes 5-exo-trig cyclization to af- Ph Ph Ph Ph ford a spirocyclic species 22.8. This spirocyclic intermediate 84% 83% 92% 94% 48% is then oxidized by either BPO or the benzoyloxyl radical Scheme 23 Scope of the reductive acylation of electron-deficient 22.13 to form a carbocation 22.9. 1,2-Ester migration and alkenes catalyzed by Eosin Y21 deprotonation afforded the desired product 22.11. Oxida- tion of AQH• by BPO, followed by deprotonation produced Anionic Eosin Y is commonly engaged in SETs under benzoic acid, the benzoyloxyl radical and the ground state photoredox-catalyzed conditions. However, neutral Eosin Y, AQN catalyst. This reaction also proceeds under thermal which was used by Wu et al.,21 is inactive in SET processes.38 conditions, where a 54% yield was obtained in the absence It was shown that neither THF nor phenyl vinyl sulfone of the photocatalyst, indicating that the benzoyloxy radical quenches the excited Eosin Y indicating that the reaction formed from the thermal decomposition of benzoyl perox- did not proceed through single-electron transfer or energy ide can also function as an alternative HAT reagent. transfer. Transient absorbance experiments showed that the excited *Eosin Y absorbs at both 329 nm and 543 nm, Ph whereas Eosin Y-H absorbs at 366 nm. In the presence of phenyl vinyl sulfone, a radical acceptor, the decay of Eosin O O O Ph Y-H was much faster than took place in the absence of the O O 22.6 Ph alkene (Scheme 24), demonstrating the feasibility of HAT Ph H Ph SET O O 22.4 22.5 22.7 AQN* 22.2 AQH 22.3 O O O Ph Ph OH Ph O Ph This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 22.12 22.13 CO2H CO2H CO2H SET O 22.1 O Br Br Br Br Br Br AQN O 22.8 O O Ph O HO O O HO O O HO O OH BPO or 22.13 BPO Ph Br Br Br Br Br Br O Ph O Ph O Ph Eosin Y *Eosin Y Eosin Y-H Ph Transient absorbance in THF solvent Ph Ph + *Eosin Y O O O O O O + hν 329 nm Eosin Y Eosin Y-H 543 nm 22.11 22.10 1,2-ester migration 22.9 366 nm 20.6 μs 4 ms O O OH tBu tBu tBu 1 ms lifetime *Eosin Y hν Eosin Y-H Eosin Y 329 nm 543 nm 366 nm O O O O Ph S AQN* AQH AQN O

Scheme 22 Photoredox-catalyzed coumarin formation from aldehydes Scheme 24 Lifetime of the transient absorbance of excited Eosin Y and via acyl radical intermediates36 the Eosin Y-H intermediate21

Syn thesis A. Banerjee et al. Review between Eosin Y-H and radical intermediates formed spectively), benzaldehydes coupled with long-chain ali- during the coupling process. The quantum yield of the reac- phatic alkenes to deliver the hydroacylated products in 67– tion was estimated to be 0.40. 89% yields. On the basis of these mechanistic studies, Wu et al. pro- O Methylene Blue (2.50 or 0.50 mol%) O O posed the direct photocatalytic hydrogen atom transfer K2S2O8 (2.00 or 1.00 equiv) O 1 + 2 21,39 R H R R1 R2 or R1 R2 mechanism shown in Scheme 25. Photoexcitation of K2CO3 (2.50 M) H2O, 25 °C, 12 h 75–92% 67–89% Eosin Y (25.1) affords excited *Eosin Y (25.2), which ab- 2.00 equiv 1.00 equiv Household bulb (100 W) R1 = aryl, cyclohexyl; R2 = aryl, pyridinyl, R2 = aryl, pyridinyl R2 = alkyl stracts an aldehyde hydrogen atom to form an acyl radical or R1 = aryl; R2 = alkyl species 25.5 and Eosin Y-H (25.3). The acyl radical is subse- CF O O O O 3 O O O O quently trapped by an electron-deficient alkene to form the Cl alkyl radical intermediate 25.7. At this stage, there are two 82% 88% 84% 79% reaction pathways accounting for the formation of the de- O O O O O O sired product and regeneration of the Eosin Y catalyst. In Me Me 6 4 path a, a reverse hydrogen atom transfer (RHAT) between N Cl MeO Me the Eosin Y-H and radical species 25.7 affords the final 91% 83% 69% 87% product and the Eosin Y catalyst. In path b, aldehyde 25.4 Scheme 26 Epoxyacylation and hydroacylation using methylene blue undergoes HAT with the radical species 25.7 to form the de- as the photocatalyst and persulfate as the oxidant40 sired product 25.8 and an acyl radical 25.5. The acyl radical reacts with Eosin Y-H via RHAT to afford an aldehyde and regenerate the Eosin Y catalyst. Although the authors per- The reaction of benzaldehyde and styrene using K2S2O8 formed computational and deuterium labeling studies, they in the absence of K2CO3 only afforded trace acyl-epoxylated could not distinguish between these two pathways. product, whereas the reaction proceeded well using H2O2 in

the presence of K2CO3. Based on these observations and lit- O erature precedents,41 a reaction mechanism involving a hy- O CN O CN R H path b R CN R CN droperoxide anion as a HAT reagent was proposed and is Ph Ph shown in Scheme 27. Persulfate anion 27.1 reacts with wa- O 25.7 25.8 25.5 ter under basic conditions to generate the hydroperoxide R RHAT red 42 anion 27.2 (E1/2 = –0.88 V vs SHE), which undergoes sin- path a red gle-electron oxidation with excited MB* (E1/2 = –1.21 V vs CO2H O Br Br SHE) to form a hydroperoxyl radical (27.3) and methylene R H CO H • • 2+ 25.4 2 CN blue neutral radical MB . Oxidation of MB by the S2O8 or HO O O Br Br Br Br CN O2 regenerates the methylene blue catalyst. The hydroper- Eosin Y HO O OH Ph 25.1 oxyl radical abstracts an aldehyde hydrogen atom to form Br Br 25.6 Eosin Y-H an acyl radical 27.6, which adds onto an alkene to give the 25.3 alkyl radical intermediate 27.8. With the lower loading of

O the photocatalyst and oxidant, the alkyl radical 27.8 under- CO2H SET R goes HAT with an aldehyde substrate to afford the desired Br Br 25.5 hydroacylation product 27.9 via a radical-chain propaga- HO O O Br Br O *Eosin Y R H Low MB and S O 2– loading 25.2 25.4 2 8 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Chain propagation 21 H Scheme 25 A direct HAT process photocatalyzed by Eosin Y 2O2 O 27.5 R2 O O O 27.7 R1 H O HAT R1 H R1 R1 R2 R1 R2 Salles et al., in 2018, achieved acyl-epoxylation and hy- 27.6 27.8 27.9 27.4 HOO droacylation of alkenes using methylene blue (MB) as a 27.3 MB* SET HOO – 3 H+ + 2 SO 2–+ HOO photoredox catalyst and K2S2O8 as an oxidant in air-equili- 4 OH O 40 27.2 • O O K2CO3 O brated water solution (Scheme 26). With high loading of MB MB R1 R2 R1 R2 2– the photocatalyst and oxidant (2.50 mol% and 2.00 equiv, S2O8 + 2 H2O 27.10 27.11 27.1 2– High MB and S2O8 loading 2– respectively), simple benzaldehydes with the arene moiety S2O8 or O2 substituted with Me, Cl, F, MeO or CF reacted with styrenes Methylene Blue 3 N N or 2-vinylpyridine to afford the desired epoxide products in Me Me Me Me N S N N S N 75–92% yields. 1-Naphthaldehyde and cyclohexanecarbox- Me Me Me • Me MB aldehyde were also viable substrates forming the final MB products in 84% and 79% yields. With lower loading of the Scheme 27 Proposed mechanism for acyl radical formation catalyzed 40 photocatalyst and oxidant (0.500 mol% and 1.00 equiv, re- by methylene blue

Syn thesis A. Banerjee et al. Review tion process. With a higher loading of the photocatalyst and A series of studies was conducted to examine the reac- persulfate anion, the alkyl radical 27.8 is trapped by the hy- tion mechanism. For example, cyclic voltammetry (CV) ex- droperoxyl radical to deliver the β-peroxyl adduct 27.10. Fi- periments on an α-keto acid salt (PhCOCO2K) suggest an ox- nally. base-promoted elimination affords the desired epox- idative decarboxylation path, TEMPO-trapping experiments ide product 27.11. confirm the formation of an acyl radical, and DFT calculations support the reaction between aroyl radicals and amines followed by deprotonation leading to an amide rad- 4 α-Keto Acids as a Source of Acyl Radicals ical anion. Interestingly, in the absence of the α-ketocarboxylic acid, EPR studies of this photocatalytic reaction detect- + Conversion of α-keto acids into the acyl radical equiva- ed two peaks: [Ru(phen)3] and an amine radical. Addition lents can be achieved via single-electron transfer of the cor- of an α-ketocarboxylic acid diminishes the organic radical + responding carboxylate by photocatalytic oxidation and peak and only the [Ru(phen)3] peak remains. Thus, the au- + subsequent decarboxylation. Alternatively, installation of a thors proposed that the oxidation of [Ru(phen)3] by molec- good leaving group (X), e.g., as in N-hydroxyphthalimide, ular oxygen is crucial and probably the rate-determining generates a keto ester that can be reduced by a photoredox step of this process. Based on these results, a possible reac- catalyst (PC) and forms an acyl radical after further decar- tion mechanism was proposed and is shown in Scheme 30. boxylation (Scheme 28). Reductive quenching of the excited photocatalyst 2+ *[Ru(phen)3] by an amine forms an amine radical cation O O + – H – oxidation OH O 30.2 and [Ru(phen)3] . Single-electron oxidation of R base R O O + – CO2 [Ru(phen) ] by molecular oxygen affords the ground state O O PC O 3 SET R R O O photoredox catalyst, [Ru(phen) ]Cl , and a superoxide radi- X reduction O 3 2 OH O R R X cal anion, which deprotonates and oxidizes the ammonium O O α-ketocarboxylate salt 30.3 to produce the dicarbonyl radi- Scheme 28 Generation of an acyl radical from α-keto acids by pho- cal intermediate 30.5. Decarboxylation of 30.5 gives acyl toredox catalysis radical 30.6, which is then trapped by amine 30.1 followed by deprotonation in the presence of a hydrogen peroxide – In 2014, Lei and Lan reported the first visible-light-me- anion HO2 (30.4) to produce the amide radical anion 30.7. diated photocatalytic oxidative decarboxylation of α-keto Oxidation of 30.7 via a SET process affords the desired am- acids in the synthesis of amides.43 This efficient radical de- ide product 30.8. carboxylative coupling was catalyzed by the photocatalyst II*/I 44 + [Ru(phen)3]Cl2 (E1/2 = +0.82 V vs SCE) and molecular ox- R2NH2 30.2 O2 1+ ygen as an oxidant. A wide range of electron-donating and [Ru(phen)3] 1 2 R COCO2H-NH2R CO2 electron-withdrawing aromatic α-keto acids reacted 2 30.3 R NH2 SET – O 1 smoothly under these reaction conditions to afford the de- 30.1 2 R COCO2 R1CO

– 2 30.5 30.6 2+ 2+ HO2 + R NH2 sired amides in good yields (64–85%) (Scheme 29). Het- *[Ru(phen)3] [Ru(phen)3] 30.1 eroaromatic and aliphatic α-keto acids provided the desired 30.4 30.1 + 30.4 H2O2 products in 48–40% yields. Various electron-rich aromatic SET 1 2 and aliphatic amines gave the corresponding products in R CONHR R1CONHR2 40–79% and 25–77% yields, respectively. 30.8 30.7 Scheme 30 Mechanism for the amidation from α-keto acids and 43 [Ru(phen) ]Cl (1.00 mol%) amines O 3 2 O 25 W household light This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. OH H N R2 R1 + 2 2 1 R DMSO (0.250 M) R N H O 32 °C, 36 h, O2 1.00 equiv 1.50 equiv This method was also applied to anilines, o-substituted 1 2 R = (hetero)aryl, alkyl; R = aryl, alkyl with NH , OH, and SH groups, to construct important het- Me 2 O Me Me Me O O O erocyclic compounds such as benzimidazoles (68–93%), N N N Me N H H H benzoxazoles (39–46%), and a benzothiazole (32%) in good S H 85% 81% 48% 40% SMe yields (Scheme 31). O O O O Following initial studies by Lei and Lan on photoredox- N N N N H H H H catalyzed decarboxylative amidation,43 this acyl radical a b 61% 56% 76% 25% generation from α-keto acids has been employed in several Scheme 29 Visible-light-mediated decarboxylation/oxidative amida- radical coupling reactions. For example, in 2015, Macmillan tion of α-keto acids with amines.43 a Using 10 equivalents of amine. b et al. reported the first decarboxylative arylation of α-keto Using 5 equivalents of amine acids using aryl halides via a merger of visible-light pho-

Syn thesis A. Banerjee et al. Review

O The authors proposed that the strongly oxidizing excit- [Ru(phen)3]Cl2 (1.00 mol%) OH H2N N + III*/II 2 25 W household light R1 + R R2 ed *[Ir(dF(CF3)ppy)2(dtbbpy)] (34.2) (E1/2 = +1.21 V vs O HX DMSO (0.250 M) R1 X SCE in MeCN),46 generated upon visible-light irradiation, re- 1.00 equiv 1.50 equiv 32 °C, 36 h, O2 1 2 R = H, OMe, CF3, halogen; R = H, Me; X = N, O, S acts with the α-ketocarboxylate via single-electron oxida-

N N N N tion to generate the corresponding carboxyl radical species MeO N N O S and the reduced photocatalyst 34.4. This carboxyl radical H H 93%90% 39% 32% species subsequently delivers the acyl radical species 34.5 II Scheme 31 Benzoyl radicals from α-keto acids for the synthesis of 2- via decarboxylation. SET from the strong reducing Ir spe- 43 III/II 46 arylbenzazoles cies 34.4 (E1/2 = –1.37 V vs SCE in MeCN) to the in situ generated NiI–dtbbpy complex would afford the Ni0 catalyst 34.6, which initiates the second catalytic cycle through oxi- toredox catalysis and nickel catalysis.45 Substituted aromat- dative addition to the aryl halide to generate the NiII aryl ic and aliphatic α-keto acids are compatible under the reac- complex 34.8. The addition of the nucleophilic acyl radical tion conditions and provide moderate to excellent yields 34.5 to 34.8 produces the nickel acyl complex 34.9. Final re- (57–92%) of the desired ketones (Scheme 32). A sterically ductive elimination from this NiIII complex provides the de- hindered o-substituted α-keto acid was also efficiently cou- sired ketone 34.10 with the regeneration of the NiI–dtbbpy pled under the same reaction conditions and provided the complex 34.11 (Scheme 34). desired product in high yield (92%). Halo-arenes (halo = Br, O I) and halo-heteroarenes containing electron-donating and O R1 34.5 electron-withdrawing substituents also provided the de- O R1 R2 I 34.10 R1 COOH II I sired ketones in 70–90% and 64–85% yields, respectively. 34.3 Ir Ni Ln SET 34.4 34.11 + I – H , – CO2 O 2 III O [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1.00 mol%) R Ni Ln X NiCl (dtbbpy) (10.0 mol%) 2 1 HO 2 2 R COR + R Photoredox Nickel 34.9 Y Li2CO3 (2.00 equiv), r.t., 72 h Y catalytic cycle SET catalytic cycle 1 O 1 R 34 W blue LED, DMF (0.020 M) R *IrIII 1.00 equiv 2.00 equiv H 34.2 2O (2.00 equiv) O R1 = (hetero)aryl; R2 = aryl, alkyl; X = Br, I; Y = CH, N I III 1 Ir L Ni0 2 II R 34.1 n R Ni Ln X = I 34.6 34.5 O O Me O O 34.8 Ph R2I Me Me Me Me Me Me 34.7 88% 92% 88% 92% O X = Br O O O Scheme 34 Proposed mechanism of ketone formation from α-keto acids and iodoarenes45

N Cl Ac F C N 90% 73% 80% 3 80% In the last decades, palladium has been widely used in Scheme 32 Decarboxylative arylation of α-keto acids using metalla- various transition-metal-catalyzed decarboxylative cross- 45 photoredox chemistry coupling reactions.47 A typical example is the decarboxylative acylation of aryl halides using α-keto acids.48 In 2015, Further generalization of this method was demonstrat- Shang and Fu combined photoredox and palladium cataly- ed by successfully coupling hindered vinyl halides and cy- sis and achieved such decarboxylative cross-coupling reac- clopentyl bromide with α-keto acids under the optimized tions for the first time.49 The reported decarboxylative cou- reaction conditions to generate a vinyl ketone and a dialkyl pling strategy of aryl halides with α-ketocarboxylic acids

ketone in good yields (73–88%). This strategy was also elab- provides access to various unsymmetrical ketones. The This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. orated for the synthesis of fenofibrate, a cholesterol-con- electronic and steric effects of the substituents present in trolling drug (Scheme 33). aryl halides have no substantial effects on the yields of the products (74–96%). Interestingly, aryl iodides containing a O O Me Br standard Me O tBu t-butoxycarbonyl (Boc)-protected phenylalanine ester and HO tBu conditions t Br or+ Bu or Me Me an aryl boronic pinacol ester both provided the correspond- O vinyl bromide alkyl bromide keto acid vinyl ketone dialkyl ketone ing products in 88% and 70% yields. This reaction is compat- 73% yield 88% yield ible with electron-donating aryl groups (82–95%) as well as O O 3 steps in total I standard HO conditions heteroaryl (46–89%) and alkyl α-ketocarboxylic acids (60– + Me Me Me Me O OiPr 71% yield OiPr Cl O Cl O 89%), but the presence of electron-withdrawing substitu- O fenofibrate O ents on the aryl ring of the α-ketocarboxylic acids sharply Scheme 33 Scope of the decarboxylative arylation strategy45 decreased the product yield to ~10%. The use of an external phosphine ligand (NiXantphos) in the case of bromoarenes is due to their relatively slow oxidative addition to the Pd0 catalyst when compared to iodoarenes (Scheme 35).

Syn thesis A. Banerjee et al. Review

X O O α-ketocarboxylic acids all coupled with acetanilide and pro- Conditions A or B HO + 2 2 Y R 36 W blue LED R vided the desired products in 70–84% and 51–62% yields, 1 R O 20 h, r.t. Y 1 1.00 equiv 2.00 equiv R respectively (Scheme 37). o-Substituted aryl α-ketocarbox- R1 = (hetero)aryl; R2 = (hetero)aryl, alkyl; Y = CH, N ylic acids were also compatible with these reaction condi- Conditions A (X = Br) Conditions B (X = I) tions providing good yields of the o-acylated products (78– [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2.00 mol%), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1.00 mol%) [Pd(PhCN)2Cl2] (2.00 mol%), DMF (0.080 M) Pd2(dba)3 (1.00 mol%), DMA (0.080 M) 85%). A range of electron-donating and electron-withdraw- NiXantphos (2.00 mol%), NaOAc (2.00 equiv) K2HPO4 (2.00 equiv) ing acetanilide derivatives all afforded the desired products O O O O in good yields (68–82%) when coupled with α-ketopheny- Ph BocHN Ph Ph Ph Me O lacetic acid. However, more hindered o-substituted acetani- B F N F3C MeO2C Me X = I, 92% X = I, 88%O X = I, 70% X = I, 90% X = Br, 88% lides such as o-ethyl, o-(isopropyl), and (o-t-butyl) acetani- Me Me O O O O lides failed to afford the o-acylated products under the re- Me ported conditions. O Me CF3 Me Me Me X = I, 10% X = I, 89% X = I, 88% X = I, 89% Pd(OAc) (5.00 mol%) O H O 2 PhCl (0.250 M), r.t., 15 h 3 1 HO R Scheme 35 Ir-Pd metallophotoredox catalysis for ketone synthesis us- R + R3 R1 2 Eosin Y (3.00 mol%) ing α-keto acids49 NHR O NHR2 1.00 equiv 1.50 equiv 3 W green LED, O2 1 t 2 i t 3 R = Me, OMe, Bu, COMe, CF3, halogen; R = COMe, CO Pr, CO Bu; R = aryl, alkyl O O O O Radical trap experiments showed that addition of 4 F3C Ph Ph Ph Ph equivalents of TEMPO completely shut down the reaction NHAc NHAc NHAc NHCOiPr and a stoichiometric amount of the corresponding TEMPO 80% 68% 68% 82% adduct was isolated (Scheme 36). These experiments O Me O O O Me strongly suggest a radical mechanism in which the excited Me Me NHAc III NHAc NHAc NHAc iridium catalyst (*Ir ) oxidizes the α-ketocarboxylate to 85% 81% 62% 51% generate the acyl radical and IrII species. Although in this context the oxidation of IrII is possible by either the PdI, PdII Scheme 37 Anilide-directed decarboxylative o-acylation using Pd-or- 50 or PdIII species, DFT calculations support the involvement of ganic photoredox chemistry the PdIII species 36.9. On the basis of TEMPO trapping experiments and con- O [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (1.00 mol%) •– HO O O firmation of a superoxide radical anion (O2 ) by electron Ph Pd2(dba)3 (1.00 mol%) + Ar-I + Ar Ph O K2HPO4 (2.00 equiv), 25 °C, 36 W blue LED TEMPO Ph paramagnetic resonance (EPR), the authors proposed a DMA (0.080 M), 20 h, TEMPO (4.00 equiv) 1.00 equiv 2.00 equiv <5% 199% plausible reaction pathway shown in Scheme 38.50 The ex- Ar = 4-MeC6H4 cited *Eosin Y (38.2) oxidizes arylglyoxylic acid 38.3 to form O (Eosin Y)•– (38.5) and arylglyoxylic radical cation 38.4, 1 36.5 O R 1 which undergoes deprotonation and decarboxylation to COR O R1 COOH II R2 PdIII •– 36.3 Ir 1 give aroyl radical 38.8. (Eosin Y) is oxidized by molecular SET 36.4 X R 36.5 + 36.9 oxygen regenerating Eosin Y and producing the superoxide – H , – CO2 2 II R Pd •– X radical anion O2 (38.6) The Pd-catalytic cycle is initiated Photoredox Palladium 36.8 catalytic cycle SET catalytic cycle by C–H activation of acetanilide forming a palladacyclic in- *IrIII 36.2 termediate 38.7, which subsequently reacts with the nucle-

1 III III COR ophilic aroyl radical 38.8 to afford a Pd intermediate 38.9. Ir 0 R2X R2 PdII Pd 36.1 36.7 III 36.10 36.6 This Pd intermediate is further oxidized by the superoxide This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. IV O radical anion to generate a Pd intermediate 38.10 along

1 2 – R R with the formation of HO2 and H2O2. Finally, reductive 36.11 elimination of the PdIV intermediate affords the desired Scheme 36 Mechanism for ketone synthesis using Ir-Pd metallopho- product 38.11 and an active PdII catalyst for the next cata- toredox catalysis49 lytic cycle. By merging Pd catalysis with organic photocatalysis, the Merging transition-metal-catalyzed o-directed C–H same group further developed a protocol for efficient ortho bond activation with photochemically generated radical in- C–H acylation of azo and azoxybenzenes by α-keto acids in termediates in a dual-catalytic fashion is an attractive strat- 2016 (Scheme 39).51 A range of aromatic as well as het- egy with which to form the desired bonds in a shortened eroaromatic α-ketocarboxylic acids reacted with azoben- and mild reaction pathway. In 2015, Wang and Li disclosed zene under the optimized reaction conditions and provided a protocol for room-temperature decarboxylative o-acyla- coupled products in 66–79% and 62% yields, respectively. tion of acetanilides with α-ketocarboxylic acids via a novel Naphthyl α-ketocarboxylic acids gave the desired products Eosin Y/Pd dual catalysis.50 Various aromatic and aliphatic

Syn thesis A. Banerjee et al. Review

Trapped by posed a mechanism that begins with the photoexcitation of O + O + O O – H , – CO2 TEMPO HO HO Ar Ar Ar TEMPO Ar mesityl acridinium catalyst (PC) 40.1 generating the excited 38.8 O 38.3 O 38.4 SET photocatalyst (*PC) 40.2. Oxidation of 40.2 by molecular ox- OAc •+ AcO COAr ygen affords PC 40.3 and a superoxide radical anion. Sub- – Pd Pd *Eosin Y Eosin Y O O sequently, 40.3 oxidizes the α-ketocarboxylic acid to regen- 38.2 38.5 Photoredox N Me N Me catalytic cycle H H erate the ground state photocatalyst PC along with the cor- 38.7 38.9 – O2 responding carboxyl radical species that leads to the

Eosin Y O2 Palladium HOAc formation of an aroyl radical species 40.5. On the other side, SET catalytic cycle – 38.1 HO2 HOAc a Pd catalytic C–H activation of the azobenzene forms the

– H2O2 palladacyclic intermediate 40.6. Addition of the in situ gen- Detected O2 H OAc by ESR AcO COAr 38.6 O Pd erated radical 40.5 to this palladacyclic intermediate 40.6 O N Me IV III Pd(OAc)2 affords the Pd or Pd species 40.7 in analogy to the obser- H N Me O H vation of Wang and Li in Scheme 38. At this stage, reductive 38.10 Ar elimination from 40.7 affords the desired acylated product 38.11 I NHAc 40.8 with the formation of the Pd intermediate 40.9, which Scheme 38 Proposed mechanism for photocatalytic decarboxylative is further re-oxidized by the superoxide radical anion to re- o-acylation50 generate the PdII catalyst, completing the catalytic cycle (Scheme 40). in 77–84% yields. However, no reaction was observed when R2 N N aliphatic α-oxocarboxylic acid was used as the acyl surro- R1 HTFA gate. Disubstituted azo- and azoxybenzenes also afforded H R2 the desired o-acylated products in decent yields (57–78%) O 2– Pd(TFA)2 N *PC 2 O2 N R1 regardless of their electronics, however, o-disubstituted 40.2 40.6 SET Pd azo- and azoxybenzene derivatives gave lower yields (37– – TFA O2 40.5 Photoredox Palladium 56%) due to steric problems. PC1+ PC catalytic cycle catalytic cycle 40.1 40.3 R2 Pd(TFA) N 40.9 1 N 2 R R 40.7 R2 N SET Pd N O N R1 – H+ TFA 1 N O O O 3 R O Pd(TFA)2 (5.00 mol%) – CO2 R 3 OH 3 or HO PC (2.00 mol%) R3 or R R R3 2 + 1.5 W blue LED, r.t., 16 h 40.4O 40.5 R O 2 O N R O toluene (0.100 M) R2 N N R1 N N 1 N 3 40.8 R R1 COR 1.00 equiv 1.20 equiv O PC = 9-mesityl-10-methylacridinium R3 Scheme 40 Proposed mechanism for photocatalytic decarboxylative 1 2 3 R , R = H, Me, OMe, iPr, tBu, CO2Et, COMe, halogen; R = (hetero)aryl o-acylation of azobenzene. Adapted with permission from ref 51. Copy- CO Et iPr 2 right (2016) John Wiley & Sons N N N N N N N N O O iPr O O 78% 52% Me 63% 77% Acyl radicals, generated by photocatalytic decarboxylation, were also reported by Shang and Fu in 2015 for acyl OMe O O Me O N N reductive Michael addition with various Michael accep- N N N N N N 52 O O O O Me tors. Various aromatic and heteroaromatic α-ketocarbox- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. MeO 62% 76%a 71%a 37%a ylic acids were decarboxylated in the presence of photore- S dox catalysts to form (hetero)aroyl radicals. These radicals underwent Michael addition to various α,β-unsaturated es- Scheme 39 Decarboxylative o-acylation of azo/azoxybenzenes using Pd organic photoredox chemistry. a DCE was used as the solvent51 ters, ketones, amides, aldehydes, nitriles, and sulfones to afford the corresponding products in 45–94% yields (Scheme 41). A series of mechanistic studies were conducted to es- The authors reported that the product yield was signifi- tablish the reaction mechanism.51 A TEMPO trapping ex- cantly decreased by reducing the loading of the base to a periment suggests the generation of acyl radicals. The in- catalytic amount, which demonstrates the role of the car- termolecular kinetic isotopic effect observed (kH/kD = 3.7) in boxylate anion in quenching the excited photoredox cata- the reaction identifies the C–H activation as the rate-deter- lyst.52 The reaction has been proposed to proceed via a re- mining step, and an EPR spectroscopic data confirms the ductive quenching cycle of photoexcited •– generation of a superoxide radical anion (O2 ) in the reac- *[Ir(dF(CF3)ppy)2(phen)]PF6 (42.2) by the α-ketocarboxylate tion medium. On the basis of these results, the authors pro-

Syn thesis A. Banerjee et al. Review

O 3 O O 3 O R [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2.00 mol%) OH R 1 [Ir(dF(CF3)ppy)2(phen)]PF6 (1.00 mol%) HO Selectfluor (2.50 equiv) 2 R R2 R1 EWG R2 R + EWG R1 + R1 O K2HPO4 (1.20 equiv), r.t., 9 h R2 O NaOAc (2.00 equiv), 5 W blue LED 1.00 equiv 1.50 equiv CH2Cl2/H2O (1:1) (0.250 M) MeCN/H2O (1:1) (0.100 M), 30–48 h 36 W blue LED 2.00 equiv 1.00 equiv 1 2 1 2 R = H, Me, Ph, halogen; R = (hetero)aryl R = (hetero)aryl; R = H, Me, nPr, COR, COOR, CF3 R3 = H, COOR, Ph; EWG = COR, COOR, CHO, CN, SO Ph 2 O O Br O Me O O O Ph O

Ph COOMe Ph CONMe2 Ph COPh Ph SO Ph 2 Me Me Me Me 61% 45% 88% 71% 81% Me 54% 84% O COOEt O O O O O O O O Cl Ph COOEt Ph CHO COMe COMe Me nPr Me S Me 91% 78% 65% 58% Me 53% Br 62%Me 60% Me Cl Scheme 41 Photocatalytic decarboxylative reductive acyl Michael ad- Scheme 43 Photocatalyzed domino fluorination–protodefluorination dition of olefins52 decarboxylative cross-coupling of α-keto acids with styrene deriva- tives53 as depicted in Scheme 42. The acyl radical 42.4, generated via the decarboxylation of an α-ketocarboxylate radical, The use of TEMPO under the standard reaction condi- was subsequently trapped by a Michael acceptor affording tions completely inhibited the product formation, indicat- the radical 42.6. This radical oxidizes the IrII catalyst regen- ing a radical process. The use of the oxidant t-butyl hydrop- erating the photocatalyst Ir[(dF(CF3)ppy)2(phen)]PF6 and eroxide under the standard reaction conditions was unpro- forming the anion 42.7, which readily protonates to provide ductive which rules out the possibility of benzylic the 1,4-addition product 42.8 (Scheme 42). Acrylic acid is oxidation. The absence of the base in the optimized reac- an ineffective Michael acceptor under these reaction condi- tion conditions provided the desired enone product in 10% tions due to its possible reductive quenching in competition yield along with the detection, by NMR analysis, of the fluo- with the 2-ketocarboxylate. β-Dimethylated and β-phenyl- ro-acylated product. From their observations in control ex- substituted alkene substrates are also incompatible Michael periments, Zhu53 proposed a mechanism which starts with acceptors due to their ability to form stable tertiary or ben- the visible-light irradiation of the photocatalyst II zylic radicals with a lower oxidation potential to oxidize Ir . [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 generating a long-lived excited state *IrIII 44.2 (Scheme 44). With the aid of Selectfluor, *IrIII O O OH can oxidizes the α-keto acid to give the aroyl radical species R1 R1 42.3O + 42.4 44.5, which reacts with styrene derivatives to deliver the – H , – CO2 SET R3 benzylic radical 44.6. Fluorination of 44.6 by Selectfluor R2 III EWG produces aroyl-fluorinated species 44.8 and the corre- *Ir IrII 42.2 42.5 O R3 sponding radical dication 44.7 which oxidizes the reduced II III R1 EWG Ir to the ground state Ir species, thereby completing the SET R2 42.6 photoredox cycle. Finally, the acyl-fluorinated product de- IrIII 42.1 livers the final α,β-unsaturated ketone product 44.9 via a O R3 O R3 – H+ base-mediated elimination process. R1 EWG R1 EWG R2 R2 42.7 42.8 Cl N Scheme 42 Proposed mechanism for decarboxylative reductive acyl N

Michael addition of olefins. Adapted with permission from ref 52. Copy- IrIII

44.1 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. right (2015) American Chemical Society SET Cl Cl N N N N III II *Ir Ir F 44.7 By strategically using the oxidant Selectfluor, Zhu et al. 44.2 44.4 developed a photocatalytic strategy for the synthesis of α,β- SET R1 O + O O unsaturated ketones using α-keto acids and styrene deriva- – H , – CO2 HO 2 53 R2 2 R tives in 2017. With a variety of substituents tolerated on R R1 O 44.3 44.5 44.6 both reactants, this domino fluorination–protodefluorination strategy provides access to the construction of α,β-un- O F O

2 saturated ketones in good yields (50–84%) (Scheme 43). 2- R2 base R R1 R1 Furanyl-, 2-thienyl-, and 2-naphthyl-substituted α-keto ac- 44.9 – HF 44.8 ids all reacted smoothly as the acyl surrogate and gave the Scheme 44 Proposed mechanism for enone synthesis53 corresponding α,β-unsaturated ketones in 50–57% yields.

Syn thesis A. Banerjee et al. Review

In 2016, Overman’s group reported the use of N-hy- – O O O droxyphthalimido esters for the efficient generation of al- R1 R1 R1 N CO NPhth N CO NPhth – CO2 N 2 2 – – NPhth 46.6 kyl as well as methoxycarbonyl radicals via a photoredox- R2 46.3 46.5 R2 R2 54 EWG catalyzed reductive SET. Based on this idea, in 2017, Taylor SET and Donald reported the generation of carbamoyl radicals EWG R3 EWG 3 * III IV R R3 from N-hydroxyphthalimido oxamides and used them for fac-Ir (ppy)3 fac-Ir (ppy)3 1 1 46.2 46.4 R R the synthesis of 3,4-dihydroquinolin-2-ones under mild N O N O 46.8 R2 46.7 R2 photocatalytic conditions (Scheme 45).55 This method pro- SET fac-IrIII(ppy) 3 EWG EWG vides access to a diverse collection of o-, m- or p-substituted 46.1 R3 R3 – H+ oxamides for the successful generation of 3,4-dihydroquin- R1 + R1 olin-2-ones in good yields (41–80%). However, a clear trend N O N O 46.9 R2 46.10 R2 of increasing yields was observed for oxamides containing Scheme 46 Proposed mechanism for the photocatalytic synthesis of electron-withdrawing substituents compared to their elec- 3,4-dihydroquinolin-2-ones. Adapted with permission from ref 55. tron-donating counterparts. Several mono- and disubsti- Copyright (2017) American Chemical Society tuted alkenes, as well as exocyclic alkenes, all afforded the desired 3,4-dihydroquinolin-2-ones containing fused cyclic R3 R4 3 (38–81%) and spirocyclic systems (43–71%). O R 1 [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2.00 mol%) R R1 OH + R4 N 36 W blue LED, 30 °C, 40 h N O EWG 2 1 O O R O CH2Cl2/H2O (2:1) (0.050 M) 2 R R3 1.00 equiv 3.00 equiv R O EWG fac-Ir(ppy) (2.00 mol%) N N 3 R1 R1 = H, Me, OMe, CF , halogen; R2 = Me, Bn, allyl 2 + toluene (0.040 M), 24 h 3 R O R3 N O 3 t n 4 O 60 W blue LEDs, r.t. R = COEt, CONMe2, CO2Me, CO2Et, CO2 Bu, CO2 Bu, CN, SO2Ph; R = H, Me 1.00 equiv 1.50 equiv R2 CN 1 2 CO2Bu CONMe2 Me CO2Me R = H, Me, OMe, CF3, halogen; R = Me, Bn, allyl 3 R = H, Me; EWG = COEt, CO2Me, CO2Et, CN, SO2Ph O N O N O N O N O CO2Et (EtO) OP CO Et SO2Ph 53% 32% 31% 54% 2 2 Me Me Me Me Me O H CO Et CO2Et Me CO2Me 2 N O N O N O N O O F C Me Me 43% 73% 59% 38% 3 Me Me Me Me >19:1 dr O N O N O N O N O 41% 45% 74% 58% Me CO Me Me Me Bn Allyl Me CO2Me Me CO2Me 2 O F3C Cl Scheme 47 Photocatalytic synthesis of 3,4-dihydroquinolin-2(1H)- N O N O N O N O 80% 54% 45% 53% 57 Me Bn Allyl Me ones using oxamic acids

Scheme 45 Photocatalytic intermolecular addition/cyclization for the synthesis of 3,4-dihydroquinolin-2-ones55 hydroquinolin-2(1H)-ones (Scheme 47).57 A variety of electron-donating and electron-withdrawing oxamic acids are compatible with the reaction under the optimized condi- The proposed mechanistic cycle begins with the irradia- tions, affording a wide variety of 3,4-dihydroquinolin- tion of the photocatalyst fac-Ir(ppy)3 with visible light, 2(1H)-ones in moderate (41–74%) yields. A range of mono, which could lead to the photoexcited state fac-*Ir(ppy)3 disubstituted and exocyclic alkenes are compatible with IV/III* 56 (46.2). Excited fac-*Ir(ppy)3 (E1/2 = –1.73 V vs SCE) re- these reaction conditions leading to the desired products duces the N-hydroxyphthalimido oxamide 46.3 to form the containing fused cyclic (31–60%) and spirocyclic systems radical anion 46.5, which rapidly fragments releasing CO2, (41%). –

NPhth , and the carbamoyl radical 46.6. The carbamoyl rad- From the reaction of N-methyl-N-phenyloxamic acid This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ical undergoes Michael addition to an electron-deficient with ethyl acrylate under the standard conditions, a trace olefin followed by cyclization to produce cyclohexadienyl amount of N-methyl-N-phenylformamide was isolated, and IV/III radical 46.8. Oxidation of 46.8 by the photocatalyst (E1/2 the addition of the radical scavenger TEMPO to the stan- = +0.77 V vs SCE)56 forms cyclohexadienyl cation 46.9, dard reaction mixtures gave only a trace amount of the de- which is deprotonated and rearomatized to give 3,4-dihy- sired product. Both of these results indicate the formation droquinolin-2-one 46.10 along with simultaneous regener- of a carbamoyl radical in the reaction medium. On the basis ation of the ground state IrIII catalyst (Scheme 46). of these results, the authors proposed a mechanistic cycle In contrast to the earlier reductive approach to the gen- in which the photoexcited catalyst *IrIII 48.2 undergoes a re- eration of a carbamoyl radical from an oxamide (Scheme ductive quenching to generate IrII and carbamoyl radical in- 45), Feng et al. reported, in 2018, a photocatalytic oxidative termediate 48.5 (Scheme 48). Analogous to Scheme 46, ad- decarboxylation approach by taking oxamic acids as the dition of the carbamoyl radical to the electron-deficient carbamoyl precursor for the synthesis of analogous 3,4-di- olefin followed by intramolecular cyclization forms a cyclohexadienyl radical intermediate 48.7. Final oxidation of reduced IrII by molecular oxygen affords the ground state IrIII

Syn thesis A. Banerjee et al. Review and a superoxide radical anion, which abstracts a hydrogen NMR studies and the formation of alkynylation products atom from cyclohexadienyl radical 48.7 to deliver the de- using a BI-keto acid complex in place of α-keto acids and BI- sired 3,4-dihydroquinolin-2(1H)-one 48.8. OAc, under otherwise identical reaction conditions, confirms the formation of a BI-keto acid complex in the reac- 3 R R3 R4 R3 R4 2+ tion medium. The luminescence quenching of [Ru(bpy)3] O O R4 R1 R1 R1 R1 was much weaker in the presence of the α-keto acid com- OH N N N O N O pared to BI-OAc, indicating that BI-OAc is primarily the oxi- 48.32 48.52 48.6 2 2 R O + R R 48.7 R – CO2, – H – dative quencher in this reaction. In accordance with obser- SET O2 vations from control experiments, the authors proposed – HO2 1 * III II fac-Ir (ppy)3 fac-Ir (ppy)3 that the benziodoxole-oxoacid complex 50.6 (BI–O2CCOR ), 48.2 48.4 R3 R4 generated in situ from an α-keto acid and BI-OAc, is oxi- O2 1 III SET R dized by Ru to liberate carbon dioxide, a benziodoxole cat- III – N O + 2+ fac-Ir (ppy)3 O2 2 ion (BI or BI-OAc), [Ru(bpy)3] and the aroyl radical 50.7 48.1 48.8 R (Scheme 50).58 The aroyl radical undergoes α-addition to Scheme 48 Proposed mechanism for the synthesis of 3,4-dihydro- the BI-alkyne followed by elimination of a benziodoxolonyl quinolin-2(1H)-ones57 radical (BI•) to yield the alkynone 50.9. BI• oxidizes the pho- 2+ toexcited *[Ru(bpy)3] to complete the photoredox cycle. The combination of visible-light photocatalysis with hypervalent iodine reagents (HIR) was successfully employed O RuII O 50.1 58 R1 BI by Chen et al. in 2015 for the generation of an acyl radical. O O 50.6 This chemoselective decarboxylative alkynylation strategy Photoredox 1 OH R HIR cycle catalytic *RuII shows a broad substrate scope in terms of HIR-bound cycle 50.5 O 50.2 alkynes as well as the α-keto acids. Aryl-substituted ben- + BI-OAc or BI RuIII O ziodoxolonyl-alkynes (BI-alkynes) containing electron-do- 50.4 50.3 O – O nating and electron-withdrawing substituents as well as al- + CO2 R1 I kyl-bound BI-alkynes all reacted well to deliver the desired O 50.7 BI 50.10 BI R2 alkynylated products in 65–93% and 65–85% yields, respec- O O O I R1 R2 R1 tively (Scheme 49). The triisopropylsilyl (TIPS)-substituted BI 50.8BI 50.9 R2 BI-alkynes, which can be easily deprotected to generate ter- Scheme 50 Mechanism for alkynylation using HIR and photoredox ca- minal alkynones, also provided good (61–70%) yields of the talysis. Adapted with permission from ref 58. Copyright (2015) John Wi- desired products. Irrespective of steric and electronic ef- ley & Sons fects, substituted alkyl, aryl, and heteroaryl α-keto acids were well tolerated and afforded the desired products in 57–87% yields. Aryl α-keto acid substrates bearing sensitive In 2015, Li and Wang used a BI-OH reagent instead of BI- functional groups such as allyl esters, propargyl esters, al- OAc to activate α-ketocarboxylic acids for the successful de- cohols, and azides were also well tolerated under these re- velopment of sunlight-driven decarboxylative alkynyla- action conditions giving the desired alkynylated products in tion.59 A range of aromatic α-keto acids reacted with (bro- 62–74% yields. moethynyl)benzene under the optimized conditions to afford the corresponding alkynones in 44–76% yields. 4- O O [Ru(bpy)3](PF6)2 (2.00 mol%) O Methyl-2-oxopentanoic acid, an aliphatic α-keto acid, re- OH BI BI-OAc (1.00 equiv) R1 + R1 O 2 CH Cl (0.0500 M), r.t., 5 h This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O R 2 2 R2 I acted with a series of o-, m- and p-substituted 2-aryl-1-bro- 4 W blue LED 1.50 equiv 1.00 equiv OAc moethynes to provide the desired products in good yields 1 2 BI-OAc R = (hetero)aryl, alkyl, amine, alcohol; R = aryl, alkyl, TIPS (60–74%). Irrespective of steric and electronic effects, sub- O O O S stituted bromoacetylenes, when reacting with 2-keto-2-

N phenylacetic acid, form the desired products in 65–80% Me 74% 58% 58% Me Me Me Me yields (Scheme 51). The presence of two strongly electron- O Me O O donating groups (–OR) on the aromatic ring of the 2-keto- Me Me N Me N Me 2-arylacetic acid, such as in 2-(3,4-dimethoxyphenyl)-2-ke- Me Me Me TIPS 73% 70% Me 85% Me toacetic acid and 2-(benzo[d][1,3]-dioxol-5-yl)-2-oxoacetic acid, when reacted with (bromoethynyl)benzene afforded Scheme 49 Photocatalytic decarboxylative alkynylation using α-keto the desired products in only 15% and 13% yields, respective- acids58 ly. However, replacing the catalytic BI-OH with a stoichio-

metric amount of PhI(OAc)2 improved the yields of these two products to 52% and 64%, respectively.

Syn thesis A. Banerjee et al. Review

O O O recombines with the Br radical, and this is followed by hy- BI-OH (30.0 mol%) OH Br 1 R1 + R O drolysis to regenerate BI-OH and complete the catalytic cy- 2 PhMe (0.200 M), r.t., 8 h 2 O R sunlight R I 3.00 equiv 1.00 equiv BI-OH OH cle.

R1 = aryl, alkyl; R2 = aryl, alkyl In 2016, Wang et al. reported BI-OAc as an efficient HIR

O O Me O catalyst for the decarboxylative 1,2-acylarylation/tandem Br Me cyclization of acrylamides with α-ketocarboxylic acids in 60 74% 77% 60% the presence of only visible light (Scheme 53). Regardless Me nPr O O of steric and electronic effects, various N-methyl-N-aryl- O MeO O methacrylamides as well as aromatic ketocarboxylic acids

a O a afforded the desired products in moderate to good (58– MeO 15%, 52% 13%, 64% 44% C5H11 MeO 78%) yields. Methyl substitution at the m-position of the N- methyl-N-arylmethacrylamide provided a regioisomeric Scheme 51 Decarboxylative alkynylation of α-keto acids with bromoa- 59 a product (70%) in a 3:2 ratio, but acrylamides containing a cetylenes using sunlight. Using 2 equivalents of PhI(OAc)2 in place of BI-OH free amine or alcohol failed to a couple under the reaction conditions. Rather than N-methyl-N-arylmethacrylamides, other acrylamides such as N-ethyl-N-arylmethacrylamide The trapping of a TEMPO adduct in the presence of and N-benzyl-N-arylmethacrylamide formed the desired TEMPO and trapping of the benzoyl as well as the benzio- products in 70–84% yields. However, N-phenyl-N-arylmeth- doxolonyl radicals by BHT under the standard conditions acrylamide was unproductive under the optimized reaction confirms the formation of benziodoxolonyl and benzoyl conditions. radicals in the reaction medium. Using an equivalent R3 amount of BI-alkyne and α-keto acid, the desired product O O Me 1 O BI-OAc (20.0 mol%) O was obtained in 66% yield only in the presence of 30% of the R + OH 1 Me R3 R O O N PhCl (0.200 M), r.t., 12 h N I BI-OH (HIR) catalyst. Separately synthesized BI-keto acid O 1.5 W blue LED R2 R2 OAc (BI-OCOCOPh), when reacted with bromoacetylenes, gave a 1.00 equiv 1.50 equiv BI-OAc 1 R = H, Me, OMe, OEt, CO2Et, Ph, halogen good yield of the desired product. These results indicate the R2 = Me, Et, Bn; R3 = aryl involvement of BI-alkynes and a BI-keto acid complex in this reaction. From these mechanistic studies, it was pro- Me Me Me Me posed that BI-OH (52.1) reacts with the ketocarboxylic acid O I O O O O O O O 52.2 to form the BI-oxoacid complex 52.3 (Scheme 52). This N N N N complex generates the benziodoxolonyl radical (52.4) and a 78%Me 77%Me Ph Me 69% 76% Et ketocarboxyl radical 52.5 under irradiation by sunlight.

Subsequently, 52.4 reacts with bromoacetylene to give the Me Me Me Me O Me O O O BI-alkyne 52.7 and releases a Br radical. At the same time, O O + O O decarboxylation of 52.5 produces an aroyl radical that adds N N Me N N 84% CH2C6H4-p-Cl Me Me 60% Me to the BI-alkyne to form 52.8, which releases the alkynone 70% (3:2) product 52.9 and the benziodoxolonyl radical. This radical Scheme 53 Photocatalytic acylarylation of olefins using α-ketocarboxylic acids60 O

R1 HBr O The catalytic cycle is initiated by the reaction of BI-OAc 52.9 R2 R1 R2

and the ketocarboxylic acid 54.1 to generate the BI-keto This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. BI OH H2O BI Br BI 52.1 52.10 52.8 acid intermediate 54.2. Visible-light-mediated homolytic O

O Br 1 cleavage of the BI–O bond of 54.2 liberates CO2, a benzoyl H O R 2 OH 52.6 R1 radical 54.3, and a benziodoxolonyl radical (54.4). Addition BI BI R2 52.2 O 52.4 52.7 of 54.3 across the double bond of arylmethacrylamides 54.5 O followed by cyclization gives intermediate 54.7, which un- 1 O R BI Br R2 dergoes hydrogen atom abstraction by 54.4 to deliver the 52.3 O desired 3,3-disubstituted 2-oxindole 54.8 and BI-H (54.9). Br O O The reaction of 54.9 with the ketocarboxylic acid 54.1 liber- O R1 R1 52.5 52.6 ates hydrogen gas and generates the BI-oxo acid intermedi- O CO2 ate 54.2 for the next cycle (Scheme 54). Scheme 52 Mechanism for the photocatalytic alkynylation of α-keto acids by HIR catalysis59

Syn thesis A. Banerjee et al. Review

O trapped by radical carbonylative alkynylation giving the desired prod- OH TEMPO R3 ucts in 42–90% yield. Rather than aromatic BI-alkynes (BI = 54.1 O O O R1 Me benziodoxolonyl), tri-isopropylsilyl- and t-butyl-substitut- N Me R3 O O 54.5 R2 ed BI-alkynes also provided the desired products in moder- I R1 – CO2 3 O BI-OAc OAc R N O ate (27–56%) yields when reacted with cyclohexyl carboxyl- 54.3 R2 54.6 O ic acid (Scheme 56). Benzoic acids failed to react, which is O R3 BI likely due to the slower decarboxylation of the benzoates to trapped 54.2 O 64 detected by BHT BI aryl radicals under the reaction conditions (rate constants by HRMS 54.4 O H –1 65 2 R3 for the decarboxylation (s ): aryl carboxylic radical: 1.4 ± H Me O determined 6 64 9 OH by GC 0.3 × 10 ; alkyl carboxylic radical: 2.2 × 10 ). α-Amino- R3 R1 O O N and α-oxygen-substituted carboxylic acids were also in- 2 54.7 R BI H R3 compatible with the reported reaction conditions. 54.9 Me O 1 R O [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2.00 mol%) O N Cs CO (0.750 equiv), CO (60 bar) O BI 2 3 1 54.8 R2 + R 2 2 x 8 W blue LED, r.t., 4 h 2 R1 OH R R CH2Cl2 (0.050 M) Scheme 54 Proposed mechanism for photocatalytic acylarylation of 1.00 equiv 1.50 equiv 60 olefins R1 = alkyl; R2 = aryl, alkyl

O O O

O 5 Carboxylic Acids as a Source of Acyl Radi- 80% 62% 50% cals O O O

i t Si( Pr)3 Bu Simple and inexpensive carboxylic acids can be an alter- 56% 27% 77% native source from which to generate the acyl radical by Scheme 56 Visible-light-induced decarboxylative–carbonylative alky- visible-light photoredox catalysis (PC). Base-mediated pho- nylations of carboxylic acids63 tocatalytic oxidation, decarboxylation and further carbonylation of the in situ generated alkyl radical by carbon monoxide (CO) can afford acyl radicals. Alternatively, the car- The use of 2-cyclopropylacetic acid as the carboxylic boxylic acid is converted into its redox-active ester by the acid substrate afforded a ring-opened alkene-alkyne prod- use of an activating agent (X = active electrophile) which uct in 52% yield under the standard reaction conditions, can be reduced by the photoredox catalyst (PC) to form the which confirms the intermediacy of an alkyl radical. On the acyl radical (Scheme 55). The redox properties of some car- basis of this radical clock experiment, the author proposed boxylates and anhydrides are listed in Scheme 55.61,62 a tentative mechanism, in which the excited state *IrIII pho- III*/II 46 tocatalyst (E1/2 = +1.21 V vs SCE) 57.2 reacts with car- ox E1/2 (V vs SCE) red boxylic acid 57.3 [E1/2 (cyclohexyl carboxylate) = +1.18 V O O O 63 Me vs SCE] to form the alkyl radical 57.5 with the release of O– O– Me O– Me + Me + + N(n-Bu)4 N(n-Bu)4 N(n-Bu)4 CO2. This alkyl radical further produces acyl radical 57.6 in 1.26 1.40 1.47 the presence of carbon monoxide. Addition of this acyl rad-

– CO2 + O ical to the BI-alkyne 57.7 followed by the release of the BI – H oxidation + CO O – R base R O PC, SET O radical (57.9) provides the alkynone product 57.10. The BI R OH red II III E = –2.29 radical oxidizes Ir to regenerate the ground state Ir pho- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1/2 + R V vs SCE X O reduction X R O PC, SET tocatalyst and form the carboxylate 57.11 (Scheme 57). X = activating agent In 2015, Wallentin et al. employed for the first time the red E1/2 (V vs SCE) activating agent dimethyl dicarbonate (DMDC) to generate O O O O an acyl radical from carboxylic acids using visible-light O O OMe photocatalysis (Scheme 58).62 A range of substituted meth- –1.74 –1.01 acrylamides, when reacted with benzoic acid under the Scheme 55 General scheme for photocatalytic acyl radical formation standard reaction conditions, afforded the 3,3-disubstitut- from carboxylic acids61,62 ed 2-oxindole derivatives in good to excellent yields (74– 95%). Benzoic acids bearing substituents at the o-, m- or p- In 2015, Lu and Xiao reported a visible-light photocata- position as well as carboxylic acids with extended aromatic lytic decarboxylative–carbonylative alkynylation of carbox- systems all reacted very well (76–97%) under the optimized ylic acids with hypervalent iodine bound alkynes in the reaction conditions. Surprisingly, o- and p-methyl-, as well presence of carbon monoxide.63 A range of cyclic and acyclic as p-hydroxy- and p-trifluoromethylbenzoic acids reacted aliphatic carboxylic acids exhibited good reactivity in this

Syn thesis A. Banerjee et al. Review

Radical clock experiment [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2.00 mol%) O erated in situ from the carboxylic acid 59.3 in the presence BI Cs2CO3 (0.750 equiv), 60 bar CO IV CO2H + of DMDC and 2,6-lutidine, to produce fac-Ir (ppy)3 (59.5) 2 x 8 W blue LED, r.t., 4 h Ph 52% Ph CH2Cl2 (0.050 M) and a radical anion 59.6. Decarboxylation of 59.6 gives the O * IrIII acyl radical 59.7, which adds to the double bond of the 57.2 R1 OH 57.3 methacrylamide 59.8 and subsequently undergoes cyclization to afford intermediate 59.10. Oxidation of 59.10 by fac- IV – CO2 Ir (ppy) provides the desired product 59.11 with regener- III 3 – H+ Ir 57.1 ation of the photocatalyst fac-Ir(ppy)3 to close the catalytic COO– cycle. R1 IrII I 57.5 57.4 57.11 – BI O O O DMDC O O O O – CO2 R1 CO Me 2 57.9 R3 + BI R R3 OH base R3 O OMe R3 O OMe – OMe N O O O 2 57.7 59.3 59.4 59.6 59.7 59.8 R 1 R R1 R2 R1 57.6 57.8 BI 57.10 R2 SET

Scheme 57 Mechanism for the photocatalytic decarboxylative–carbo- * III IV 3 3 fac-Ir (ppy)3 fac-Ir (ppy)3 R R 63 nylative alkynylations of carboxylic acids 59.2 59.5 O O Me Me

1 R O R1 + O – H N N R2 2 III SET R very poorly under the standard conditions, however, after fac-Ir (ppy)3 59.10 59.9 59.1 3 replacing DMDC with Boc2O and 1 equivalent of MgCl2 and R Me increasing the loading of fac-Ir(ppy)3 to 2.5 mol%, the de- O R1 O sired products were produced in good (72–99%) yields. N 59.11 R2 These new reaction conditions [Boc2O, 1 equiv of MgCl2 and 2.5 mol% of fac-Ir(ppy) ] were very effective for heteroaro- Scheme 59 Mechanism of the visible-light-catalyzed 1,2-acylarylation 3 62 matic carboxylic acids and afforded the 1,2-acylarylation of methacrylamides products in good (33–78%) yields. In 2017, the Wallentin group merged the concept of R3 photocatalytic acyl radical formation from carboxylic acids fac-Ir(ppy) (0.500 mol%) O O O O O 3 66 R1 2,6-lutidine (50.0 mol%) Me with multicomponent reactions (Scheme 60). Strategical- Me + MeO O OMe R3 OH N DMDC (3.00 equiv), r.t., 6 h R1 O 2 ly combining electron-poor and electron-rich alkenes with R DMF (0.500 M), 8 W blue LED N DMDC 1.00 equiv 1.50 equiv R2 1 2 3 acyl radicals generated from mixed anhydrides of DMDC R = H, Me, OMe, halogen; R = Me, –(CH2)–, Ph; R = (hetero)aryl and carboxylic acids, the method was able to provide access Ph MeO CHN CF 2 3 to the synthetically challenging 1,2-dicarbofunctionaliza- NHCO2Me tion of alkenes. This strategy yielded 1,2-difunctionalized Me Me Me Me Me O O O O products in good (33–97%) yields when reacted with substi- O O O O N N N N tuted aromatic as well as heteroaromatic carboxylic acids a 89%Me Me 76% 72%a Me 99% Me with different silanol ethers and methyl acrylate. The scope S Ph Ph Ph of the reaction was further extended to other electron-poor Me Me Me Me Me O O O Cl O O O O O fac-Ir(ppy) (2.00–5.00 mol%) N Me N N N O EWG OTBS 3 O EWG O 78%a Me 92%Me 95% Ph 75% Ph 2,6-lutidine (50.0 mol%) + + R1 OH R2 R3 R1 R3 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. DMDC (3.00 equiv) R2 8 W blue LED, r.t., 48 h Scheme 58 Visible-light-mediated 1,2-acylarylation of methacryl- 2.00 equiv 2.00 equiv 1.00 equiv DMF (0.100 M) 62 a 1 2 3 amides using carboxylic acids. Using 2.5 mol% of fac-Ir(ppy)3, 3 equiv R = (hetero)aryl; R = CO2R, CONR2, CN, COR, SO2Ph; R = (hetero)aryl of Boc O and 1 equiv of MgCl over 48 h 2 2 Me Me Me O O O O O O O O O O O O Me When a mixed anhydride synthesized separately from Ph Ph a a a 94% 97% S 57% MeO the reaction of benzoic acid and DMDC reacted with meth- O Me O acrylamides under the standard reaction conditions, the O O O N O O O CN O O desired product was formed in a good yield. Stern–Volmer O b fluorescence quenching studies clearly revealed that anhy- 40%b 52%b 66% MeO MeO Cl O Ph drides quench the excited fac-*Ir(ppy)3. From these mechanistic studies, a plausible mechanism was derived and is de- Scheme 60 Photoredox-catalyzed intermolecular three-component synthesis of β-functionalized δ-diketones.66 a Using 5.00 mol% of fac- picted in Scheme 59. The photoexcited fac-*Ir(ppy)3 59.2 b IV/*III Ir(ppy)3. Using 2.00 mol% of fac-Ir(ppy)3 (E1/2 = –1.73 V vs SCE) reduces the anhydride 59.4, gen-

Syn thesis A. Banerjee et al. Review olefins beyond methyl acrylates, with these reactions af- TEMPO additives completely shut down this hydroacy- fording the desired difunctionalized products in 41–66% lation reaction, which indicates the radical nature of this yields. process (Scheme 63). The mechanism starts with the exci-

The reaction pathway for the formation of the acyl radi- tation of fac-Ir(ppy)3 63.1 to excited fac-*Ir(ppy)3 63.2 by cal 61.5 is the same as that proposed in Scheme 59. The nu- visible-light irradiation. Single-electron reduction of the cleophilic acyl radical first adds to the electron-poor olefin mixed anhydride 63.3, generated by reacting the carboxylic

61.6 forming the radical intermediate 61.7 (Scheme 61). acid with DMDC, by the excited fac-*Ir(ppy)3 forms acyl

This electron-deficient radical species reacts selectively radical 63.5 with the extrusion of CO2 and OMe. Subsequent with silyl enol ether 61.8 to deliver 61.9, which is oxidized addition of the acyl radical to the activated olefins forms IV by fac-Ir (ppy)3 and this is followed by desilylation to pro- radical intermediate 63.7. This radical intermediate then duce the desired product 61.10. quickly abstracts the proton from TMS3Si-H 63.8 to give the desired hydroacylation product 63.9. The final SET process O DMDC O O O O EWG IV between fac-Ir (ppy)3 and 63.10 regenerates the ground base R1 OH R1 O OMe R1 EWG R1 R2 61.3 61.5 61.7 state fac-Ir(ppy)3 for the next cycle. R2 OTBS SET 61.6 R3 R4 – CO 2 61.8 O DMDC O O – OMe 3 4 fac*-IrIII(ppy) IV R O R 3 fac-Ir (ppy)3 1 base 1 O O EWG OTBS R OH R O OMe R2 63.6 61.2 61.4 1 3 R1 R R R1 R3 63.3 SET 63.5 R2 R2 63.7 – CO 61.9 2 TMS3Si-H SET – OMe fac*-IrIII(ppy) fac-IrIV(ppy) 63.8 –TBS+ 3 3 HAT III O EWG O 63.2 fac-Ir (ppy)3 63.4 61.1 1 3 O H 4 R 2 R R R TMS3Si 1 3 63.10 R R 61.10 SET R2 63.9

Scheme 61 Proposed mechanism for the photoredox-catalyzed inter- III fac-Ir (ppy)3 molecular three-component synthesis of β-functionalized δ-diketones66 63.1 TMS3Si 63.11 Scheme 63 Proposed mechanism for the photocatalytic hydroacyla- Using the idea of in situ generation of anhydrides as the tion of olefin.67 Adapted with permission from ref 67. Copyright (2017) acyl radical precursors, Zhu’s group reported three photo- American Chemical Society catalytic reactions in 2017.67–69 First, they reported the photoredox-catalyzed hydroacylation reaction of olefins using Shortly after their photocatalytic hydroacylation of acti- carboxylic acids as acyl radical precursors and tris(trimeth- vated alkenes, Zhu et al. reported the selective photocata- ylsilyl)silane (TMS3Si-H) as a hydrogen atom source lytic reduction of aromatic carboxylic acids to the corre- 67 (Scheme 62). A range of electron-donating and electron- sponding aldehydes using the fac-Ir(ppy)3 and tris(trimeth- 68 withdrawing substituted styrenes, such as α,β-substituted ylsilyl)silane (TMS3Si-H) system (Scheme 64). Aromatic or unsubstituted vinyl esters, a vinyl sulfone, and an ali- carboxylic acids, regardless of the position and electronic phatic olefin all reacted well with benzoic acid to afford the properties of the substituents including free alkynyl, amide, corresponding hydroacylated products in 36–84% yields. and ester groups, reacted smoothly under the optimized re- Both aromatic and heteroaromatic carboxylic acids were vi- action conditions to afford the corresponding aldehydes in able substrates and coupled with styrene to give the desired 82–92% yields. Heteroaromatic carboxylic acids and a few products in 53–70% yields. complex aryl carboxylic acids were successfully reduced to This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. fac-Ir(ppy) (2.00 mol%) O 4 3 O H R 4 fac-Ir(ppy) (2.00 mol%) TMS3Si-H (2.00 equiv), DMDC (3.00 equiv) R O 3 + O R1 OH R3 R1 R3 TMS3Si-H (2.00 equiv), DMDC (3.00 equiv) K3PO4 (2.00 equiv), MeCN (0.050 M) 1 2 R2 R OH R1 H R 5 W blue LED, r.t., 20–24 h, Ar K2HPO4 (2.00 equiv), MeCN (0.050 M) 1.00 equiv 2.00 equiv 1.00 equiv 5 W blue LED, Ar, r.t., 6–24 h 1 2 3 4 1 R = (hetero)aryl; R = H, Me, CF3; R = aryl, CO2R, SO2Ph, alkyl; R = H, Me, CO2R R = (hetero)aryl O O O OEt O O O H O H O H O O O H H OEt OEt H H Ph Ph S Ph Ph S O H Me CF3 O Me O 92% 83% 88% 65% Cl 62% 80% 60% 84%

O N Me Me O O H O Me Me O H O H H Me O H O N Ph Ph Ph Ph Ph H H H Me HN OEt 36% 80% O S 58% 69% H H Me H O O H O 71% 82% 84% Scheme 62 Photocatalytic hydroacylation of olefins using carboxylic O acids and hydrosilanes67 Scheme 64 Photocatalytic reduction of carboxylic acids to aldehydes68

Syn thesis A. Banerjee et al. Review

TMS Si-H O DMDC O O 3 A plausible mechanism for this intramolecular radical 65.6 R1 OH base R1 O OMe O O cyclization process is shown in Scheme 67. The aroyl radical 65.3 HAT R1 R1 H 67.6 generated from the mixed anhydride 67.4 adds to the SET 65.5 65.7 – CO2 ortho position of the 2-aryl ring to give intermediate 67.7. – OMe fac*-IrIII(ppy) IV 3 fac-Ir (ppy)3 Oxidation of intermediate 67.7 by fac-IrIV(ppy) followed by 65.2 65.4 TMS3Si 3 65.8 deprotonation regenerates the ground state Ir(ppy)3 and af-

SET fords the desired product 67.8.

III fac-Ir (ppy)3 O 65.1 O O OMe O TMS3Si-OMe 65.9 OH DMDC O base Scheme 65 Proposed mechanism for the photocatalytic reduction of 2 2 2 R1 R R1 R R1 R carboxylic acids68 67.3 67.4 67.6 SET – CO 2 O – OMe * III IV fac-Ir (ppy)3 fac-Ir (ppy)3 the desired aldehydes as well. However, aliphatic carboxylic 67.2 67.5 R1 acids such as 3-phenylpropanoic acid, cyclohexane carbox- 67.7 ylic acid, and N-Boc-glycine were all unproductive under SET – H+ O III fac-Ir (ppy)3 the standard reaction conditions. 67.1

The proposed mechanism up to the formation of the 2 R1 R 67.8 acyl radical 65.5 by excited fac-*Ir(ppy)3 65.2 (Scheme 65) is the same as the hydroacylation reaction mechanism us- Scheme 67 Mechanism for the intramolecular acylation/radical cy- ing carboxylic acids (Scheme 63). Once the reactive acyl clization69 radical 65.5 is generated, it rapidly reacts with TMS3Si-H (65.6) to form the corresponding aldehyde 65.7. Regenera- In 2018, Zhu et al. merged phosphoranyl radical chemis- tion of fac-Ir(ppy)3 occurs in the final stage by the reaction try with photoredox catalysis to form acyl radicals from IV of fac-Ir (ppy)3 and 65.8. carboxylic acids via C–O cleavage using Ph3P or Ph2POEt. The third reaction developed by Zhu’s group in 2017 These acyl radicals added to alkenes and imines to give the was an efficient deoxygenative intramolecular acyla- desired hydroacylation products (Scheme 68).70 The scope tion/radical cyclization via photoredox catalysis for the syn- of the reaction is very broad. Various aryl and heteroaryl thesis of valuable fluorenone products.69 A variety of func- carboxylic acids reacted with a wide array of electronically tionalized biarylcarboxylic acids containing o- and p-sub- diverse alkenylpyridines, styrenes, and Michael acceptors stituents on the 2-aryl ring afforded fluorenones in 54–85% such as acrylate, phenyl vinyl sulfone, diethyl vinylphos- yields, while the m-substituted aromatics gave regioiso- phonate, cyclohexanone and lactones to give the desired ke- meric products. Electron-donating or electron-withdrawing tones in 38–89% yields. However, alkyl, alkenyl, and alkynyl substituents on the aromatic moiety of the carboxylic acid carboxylic acids failed to give the desired products. Notably, were well tolerated under the standard reaction conditions the reaction is amenable to late-stage functionalization of (61–86%) (Scheme 66). complex carboxylic acids and alkenes in yields of 40–76%. The reaction is also applicable to the hydroacylation of O O OH imines generated in situ under the reaction conditions to fac-Ir(ppy) (2.00 mol%), 2,6-lutidine (1.00 equiv) 3 afford α-amino-ketone products. DMDC (3.00 equiv), DMF (0.0500 M), 5 W blue LED, r.t. 2 2 R1 R R1 R Based on a series of mechanistic studies including radi- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1.00 equiv 18 1 2 t R = Me, F; R = Me, Bu, OMe, OBn, SMe, CF3, halogens cal trapping, deuterium- and O-labeling, and Stern–Vol- O O O O mer quenching experiments, a proposed reaction mechanism is depicted (Scheme 69). Photoexcited SMe Ir*[(dF(CF )ppy)] (dtbbpy)PF (E III*/II = +1.21 V vs SCE)46 * * 3 2 6 1/2 78% 71% 84%; r.r. = 7:1 Me 85%; r.r. = 6:1 OMe undergoes reductive quenching by PPh (E red = +0.98 V vs O O O O 3 1/2 OMe SCE)71 to form IrII and the triphenylphosphine radical cation F Me 69.1. Deprotonation of an aryl or heteroaryl carboxylic acid

67% 83%OMe 61% 86% by K2HPO4 forms a carboxylate, which reacts with 69.1 to form a phosphoryl radical 69.3. β-Scission of the phosphor- Scheme 66 Photocatalytic intramolecular acylation/radical cyclization yl radical 69.3 liberates triphenylphosphine oxide and aroyl of biarylcarboxylic acids;69 r.r. = regioisomeric ratio radical 69.4, which then adds to olefin 69.5 to deliver the alkyl radical intermediate 69.6. Reduction of 69.6 by IrII

Syn thesis A. Banerjee et al. Review

Ir[(dF(CF3)ppy)]2(dtbbpy)PF6 (1.00 mol%) boxylic acids, heteroaryl carboxylic acids with indole, ben- Ph P (1.20 equiv) O O Z 3 K2HPO4 (20 mol%) ZH zothiophene and quinolone, and aliphatic carboxylic acids 1 + R1 R OH R2 CH2Cl2/H2O, 5 W Blue LED 2 1.00 equiv 1.50 equiv R all reacted under the optimized conditions to form the cor- 4 5 1 2 3 Z = CR3R or NR ; R = aryl, heteroaryl; R , R = H, alkyl, ester responding aldehydes in 34–94% yields. R4 = aryl, heteroaryl, ketone, ester, benzenesulfonyl, phosphonate; R5 = aryl O O O O Ir[(dF(CF )ppy)] (dtbbpy)PF (1.00 mol%) O 3 2 6 O N OMe Ph PX (1.20 equiv), HAT (5.00 mol%) Py Py p-Tolyl p-Tolyl 2 R OH R H N N N PhMe (0.100 M), 34 W Blue LED Me CHO 1.00 equiv 78% 59% 86% 87% OMe R = aryl and heteroaryl Ph2PX = Ph3P HAT = (p-MeOC6H4)2S2 F O R = alkyl Ph2PX = Ph2POEt HAT = TRIP-SH

O CF3 OMe O H CHO CHO CHO F CHO CHO O O p-Tolyl N Ph Ph N p-Tolyl p-Tolyl COMe Ph Me MeS OMe pinB Me N 68% 47% O 79% 48% 80% 94% 86% 37%a 33%b

CHO Me Me O O O O Me N Me O O O OHC OMe p-Tolyl CHO p-Tolyl O p-Tolyl S p-Tolyl P S N Ph OEt N O O O EtO O N CHO 51% 73% 78% 69% N Me O OH Me Me Me Me 68%a 80% 45% N

N N O Me Me Scheme 70 Substrate scope of the photocatalytic deoxygenative ap- N Me O O Me Me O proach for aldehyde formation from carboxylic acids.72 a 2,6-Lutidine Me O H was added (1.00 equiv), b N-methyl-2-pyrrolidone (NMP) was used as O OMe O Me the solvent 58% O Me Me 71% O O Me Me When radical acceptors such as carbonyl and iminyl de- Scheme 68 Substrate scope of the hydroacylation of alkenes and rivatives or alkenes were ortho to the carboxylic acid group imines under photocatalytic conditions using Ph P as a deoxygenating 3 on a benzene ring, intramolecular acyl radical addition took reagent70 place to form cyclized products in 50–93% yields (Scheme 71). Aliphatic carboxylic acids could cyclize to form five- O O K HPO membered lactone and ketone products in 43% and 44% 2 4 – Ar OH Ar O yields, respectively. 69.2 O PPh3 PPh3 PPh3 O O O 69.1 Ar O O Ph3P SET 69.3 OH Ph3P OH TRIP-SH X Me X PhMe/DMF PhMe (95:5) Ir*(III) Me Me 53% 69.5 Ph2S2 X = O, 93% Ir(II) Ph3P O TRIP-SH X = NPh, 50% O R O O O O O Ph3P Ph3P SET Ar R Ar Me Ir(III) 69.4 2,6-Me2C6H3SH TRIP-SH 69.6 OH O OH O PhMe/DMF PhMe (95:5) O O O H2O O OMe – OMe 84% 58% Ar R Ar R O Ph POEt O O Ph POEt 69.7 69.8 2 2 O F HO TRIP-SH O F TRIP-SH

Ph OH This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. PhMe PhMe Scheme 69 Proposed mechanism for the photoredox-catalyzed aroy- O Ph 70 43% 44% lation of alkenes using Ph3P as a deoxygenating reagent Scheme 71 Intramolecular cyclization of acyl radicals and radical ac- 72 III*/II 15a III ceptors under photocatalytic conditions (E1/2 = –1.37 V vs SCE) regenerates the Ir photoredox catalyst and anion 69.7, which undergoes protonation to give the desired ketone 69.8. Generation of the acyl radical is similar to the mecha- Concurrently and independently, Doyle et al. (Scheme nism proposed by Zhu (Scheme 69).70 Once the acyl radical 70) applied the same concept for converting alkyl, aryl, and 72.3 is formed, it abstracts a hydrogen atom from an ar- heteroaryl carboxylic acids into the corresponding acyl rad- ylthiol 72.4 to give the desired aldehyde 72.5 and an arylth- icals,72 which abstract a hydrogen atom from arylthiols to iyl radical 72.6 (Scheme 72). Reduction of 72.6 by IrII regen- form the desired aldehydes. The scope of the reaction is erates the IrIII photoredox catalyst and thiolate 72.7, which quite general: electron-rich and electron-deficient aryl car- upon protonation forms the arylthiol 72.4.

Syn thesis A. Banerjee et al. Review

red 61 O anhydrides (benzoic anhydride: E1/2 = –1.01 V vs SCE). + O PPh3 PPh3 R OH – H The plausible mechanism is analogous to Wallentin’s previ- 72.1 PPh3 R O SET ous mechanism for 1,2-acylarylation of methacrylamide + HSAr 72.2 – H Ir(II) SAr 72.4 (Scheme 59),62 except the anhydride is directly employed 72.7 Ir*(III) here rather than being generated in situ from a carboxylic Ph3PO SET O acid.

HAT R Following the Wallentin group’s report on the direct use Ir(III) 72.3 O of anhydrides as the acyl radical surrogate under photore- SAr R H dox conditions, Ye et al., in 2017, reported the construction 72.6 72.5 of 1,4-dicarbonyl compounds using analogous symmetrical 74 Scheme 72 Proposed mechanism for the photocatalytic acyl radical carboxylic anhydrides or mixed anhydrides. A wide range 72 formation using Ph3P as a deoxygenating reagent. of symmetrical anhydrides containing electron-withdrawing or moderately electron-donating groups worked effi- 6 Anhydrides as a Source of Acyl Radicals ciently under these reaction conditions and gave the desired products in 62–79% yields (Scheme 74). However, a strongly electron-donating group like OMe lowered the Rather than the in situ formation of anhydrides from product yield to 58%. Bromo-substituted symmetrical anhy- carboxylic acids in the presence of DMDC or Boc2O, the di- drides gave lower yields (42–48%) of the desired products rect use of anhydrides is an alternate means of generating due to their poor solubility. Various olefin acceptors reacted acyl radicals using visible-light photoredox catalysis. In smoothly (40–87%) with benzoic anhydrides although the 2016, Wallentin et al. employed aromatic carboxylic anhy- α- or β-substituted olefins gave lower yields for steric or drides as the direct acyl radical source for olefinic radical electronic reasons. acylarylation under photocatalytic conditions.73 The meth- R3 3 od efficiently yielded 3,3-disubstituted 2-oxindoles (45– O O fac-Ir(ppy)3 (1.00 mol%), iPr2NEt (3.00 equiv) O R Hantzch ester (1.50 equiv) 1 98%) using a variety of symmetrical electron-withdrawing R1 O R1 + EWG R EWG R2 24 W blue LED, CH2Cl2 (0.100 M), r.t., 3 h, N2 R2 aromatic anhydrides. This protocol was also applied to vari- 3.00 equiv 1.00 equiv 1 2 3 R = (hetero)aryl; R = H, Me, Me-(CH2)4–, Ph-(CH2)2–; R = H, Me, Ph, CO2R ously substituted N-phenylacrylamides to give the corre- EWG = CO2R, CONR2, SO2Ph sponding products in 80–98% yields (Scheme 73). Interest- O O O Me O CO2Me OEt NMe2 O Ph ingly, the Lewis acid activation of more challenging elec- CO2Me O O O Ph tron-rich aromatic and heteroaromatic carboxylic 73% 48% 57% 68%a anhydrides was found to be necessary for the generation of O O O O the corresponding carbonyl radicals and the efficient syn- OBn OBn OBn OBn 71% O 79% O 79% O O 62% O thesis of the desired products in 31–95% yields. Me Cl Cl

Scheme 74 Photocatalytic hydroacylation using carboxylic acid anhy- R3 74 a 1 O O O Me drides. Reaction time was 24 h R fac-Ir(ppy)3 (1.00 mol%) O Me + 3 3 1 N R O R DMA (0.100 M), 14 h, r.t. R O R2 8 W blue LED N 1.00 equiv 2.00 equiv R2 1 2 3 R = H, Me, OMe, halogen; R = Me, Ph, –(CH2)3–; R = (hereto)aryl Radical trapping experiments with TEMPO confirmed the formation of an aroyl radical. Stern–Volmer experi- S ments, on the other hand, indicated that a Hantzsch ester is Me Me Cl Me Me

O O O O the main quencher of the photoexcited fac-*Ir(ppy)3 at low This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O O O O N N N N concentrations. However, the same excited photocatalyst Me 94% 97% Me 85%a Me 31%a Me can be quenched by higher concentrations of carboxylic an-

S hydride and iPr2NEt. Based on the above experiments, a

Me Me Me Me plausible mechanism is proposed in Scheme 75 which be- O O MeO O Cl O O O O O gins with the photoexcitation of fac-Ir(ppy)3 with visible N N N N light. The photoexcited fac-*Ir(ppy)3 75.2 undergoes single- 97% 98%Ph 94% Me 80% Me red electron transfer with the Hantzsch ester (E1/2 = +0.887 V 75 II Scheme 73 Photocatalytic 1,2-acylarylation of olefins using anhy- vs SCE) or iPr2NEt forming Ir species 75.3 and the 73 a drides. Reaction performed by adding 1 equivalent of MgCl2; reac- Hantzsch ester (HEH) or iPr2NEt radical cation (75.5 or tion time = 60 h III/II 75.4). Anhydride 75.6 is reduced by 75.3 (E1/2 = –2.19 V vs SCE in MeCN), then fragments to provide the aroyl radi- Stern–Volmer experiments indicate that the emission cal 75.7 which reacts with alkene 75.8 to form α-carbonyl IV/*III intensity of excited fac-*Ir(ppy)3 [E1/2 = –1.73 V vs SCE] was quenched significantly in the presence of symmetrical

Syn thesis A. Banerjee et al. Review

radical 75.9. The α-carbonyl radical 75.9 abstracts a hydro- electron-withdrawing groups such as CN or CF3, the desired gen atom from 75.4, 74.5, or Hantzsch ester (75.5) to deliver products were obtained in lower yields (26–60%), presum- the desired product 75.10. ably due to their higher susceptibility to reduction (for the

compound with a Me substituent: Epc = –1.77 V, CF3: Epc= – EtO C CO Et O O O 3 2 2 76 O R 1.49 V, CN: Epc= –1.36 V vs Ag/AgCl). R1 O R1 R1 1 R3 R EWG Me N Me 75.6 75.7 R2 H R3 3 EWG HEH O O R Vitamin B12 (5.00 mol%), Zn (3.00 equiv) SET 2 75.8 75.9 + 1 R 1 EWG R EWG EtO2C CO2Et R S N 2 NH4Cl (1.50 equiv), MeCN (0.100 M) – R1C(O)O– iPr + iPr R R2 N blue LED, 16 h, r.t. fac-IrIII(ppy) II + 1.40 equiv 1.00 equiv 3 fac-Ir (ppy)3 + Me N Me 75.1 75.4 1 2 3 75.3 iPr2NEt or Me H R = (hetero)aryl, alkyl; R = Me, Ph, CO2Me, CF3; R = Me, Ph; EWG = CO2R, COR, CN, SO2Ph, Ar, Py + or + HEH O O O Ph + HE O HEH 75.5 CO2Et CONMe CO2Me COPh SET 3 EtO2C CO2Et 2 O R Ph + Me Me Me Me 1 88% 58% 27% 82% fac*-IrIII(ppy) iPr2NEt R EWG Me N Me 3 H 75.2 or R2 + O O O O HEH 75.10 HE CN CN CN CN Scheme 75 Mechanism for the hydroacylation of electron-deficient S F C NC olefins74 3 60% 26% 96% 74%

Scheme 77 Vitamin-B12-catalyzed radical acylation of electron-deficient alkenes76 7 Acyl Thioesters as a Source of Acyl Radi- cals LCMS detection of the reaction aliquot showed the presence of the acyl-cobalt complex 78.4 in the medium and In 2017, Gryko et al. reported the visible-light driven vi- TEMPO trapping experiments indicated the acyl radical for- tamin-B12-catalyzed generation of an acyl radical from 2-S- mation. In the absence of the reducing agent zinc, no reac- III II pyridyl thioesters (acyl-X reagent) via a single-electron re- tion was observed using Co - or Co -vitamin B12, which duction and the subsequent reaction of an acyl radical with confirms the formation of an acyl-cobalt complex by the re- 76 I electron-deficient olefins. Scheme 76 demonstrates the action of Co -vitamin B12 generated in situ with thioesters. superiority of pyridyl thioesters compared to other acylat- Addition of ND4Cl in place of NH4Cl showed deuterium in- ing reagents employed in this reaction. The higher activity corporation at the α-position relative to the electron-with- of thioesters compared with active esters results from the drawing group, indicating the role of NH4Cl as a proton stronger electrophilic character of the carbonyl group in the source during the final step of the reaction. Light ON/OFF thioester derivatives. experiments support the formation of an acyl radical under constant irradiation of light. The proposed mechanism O O I Vitamin B12 (5.00 mol%), Zn (3.00 equiv) starts with the reduction of the thioester by Co -vitamin B12 + CO nBu n Ph X 2 Ph CO2 Bu NH4Cl (1.50 equiv), MeCN (0.100 M) (78.1) and the generation of acyl-cobalt complex 78.4 1.40 equiv 1.00 equiv blue LED, 16 h, r.t. which provides the acyl radical 78.6 under irradiation with X = O F visible light (Scheme 78). Subsequent addition of the nucle- S N S S F N N ophilic acyl radical to activated olefin 78.7 generates 78.8, N F F 73% 7% 11%F 57% which is reduced by Zn and protonated by NH4Cl to deliver II O F the desired product 78.9. The Co -vitamin B12 catalyst is re- O Ph O F I Cl O N duced to Co -vitamin B12 by Zn to complete the catalytic cy- O F F cle. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 0% 0% 5% 0% O F

Scheme 76 Investigation of various acyl derivatives76 O O R3 R1 R1 EWG O R3 2 78.6 R 1 III II Olefins bearing electron-withdrawing groups such as R Co Co EWG 78.8 2 78.4 78.5 R esters, nitriles, sulfones, amides or ketones all produced the O 78.7 Zn 1 desired ketones in 58–99% yields (Scheme 77). While α- R S N NH4Cl 78.2 Zn substituted olefins afforded the desired products in good CoI O R3

(62–82%) yields, β-substituted olefins gave lower yields 78.1 1 – R EWG S N 2 (27–47%), probably for steric reasons. Aryl, heteroaryl, and Zn R 78.3 78.9 alkyl thioesters reacted equally well under the reaction CoIII conditions and formed the desired products in 62–97% Scheme 78 Mechanism for the vitamin-B12-catalyzed reductive acyla- yields. In the case of aryl thioesters containing strongly tion of olefins76

Syn thesis A. Banerjee et al. Review

In 2018, McErlean et al. used a thioester as the acyl radi- (a) Ketyl radical dimerization cal precursor for the hydroacylation of olefins under photo- O O fac-Ir(ppy)3 (2.50 mol%) R1 77 S Bu3N (2.06 equiv) catalytic conditions (Scheme 79). With 10 equivalents of R1 Me I HCO2H (2.06 equiv) HO OH O Me tributylamine and formic acid, intramolecular acyl radical- MeCN (0.100 M) R1 1.00 equiv Blue LED, N2, r.t., 12 h olefin addition occurs to form the desired chromanone and O R1 = H, o-Cl, o-F 40% to 58% indanone derivatives in 18–71% yields (Scheme 79, a). F

When 2 equivalents of tributylamine and alkenes such as N (b) Cyclization–radical–olefin addition cyclohexene and allyltrimethylsilane were employed in the O O absence of formic acid (based on McErlean’s Supporting In- O N F fac-Ir(ppy)3 (2.50 mol%) formation), intermolecular coupling reactions took place to O Bu3N (2.06 equiv) O 24% HCO2H (2.06 equiv) afford the desired products in 10–37% yields (Scheme 79, S MeCN (0.0500 M) O I b). O Blue LED, N2, r.t., 1.25 h O N F O N F 1.00 equiv O (a) Intramolecular reactions 29% 2 fac-Ir(ppy)3 (2.50 mol%) O R 10.0 equiv O Bu3N (10.0 equiv) HCO H (10.0 equiv) 2 R1 Scheme 80 Photocatalytic ketyl radical dimerization and cyclization– 1 S R MeCN (0.0500 M) 77 I X radical–olefin addition reactions X R2 4.5 W Blue LED, N2, r.t., 1.25 h 1 t 2 X = CH2, NH, O R = H, MeO, Bu, Br; R = H, ester, cyclohexyl

O O O O O red 79 Me Br Me Me OEt Me dobenzene: E1/2 = –1.59 V vs SCE) via SET to form the O N aryl radical 81.3, which attacks the sulfur to release dihyd- O O N O H robenzothiophene (81.4) and an acyl radical 81.5. Trapping 71% 30% 68% 51% 50% of 81.5 with an olefin forms an alkyl radical intermediate 81.6, which abstracts a hydrogen atom from tributylamine (b) Intermolecular reactions radical cation 81.1, liberating the desired product 81.7. O O TMS fac-Ir(ppy)3 (2.50 mol%) O TMS Bu N (2.00 equiv) 1 or 3 R1 R S 1 MeCN (0.0500 M) R O I O O R2 1.00 equiv 51.0 equiv 4.5 WBlue LED, N2, 20 h R1 S R1 = alkyl, aryl R1 S R1 I O 81.2 81.3 81.5 O TMS Me O Me O Me O Me O Bu Me SET 81.4 Me Bu S 1 R1 R2 TMS III observed by H NMR Ir (ppy)3 IrII(ppy) 81.6 37% 3 33% 14% (1:1) 25% Bu3N 81.1 III SET Scheme 79 Photocatalytic reductive intra- and intermolecular hy- *Ir (ppy)3 Bu + Bu 77 N droacylation of olefins O Bu3N Et R1 R2 81.7 When 2.06 equivalents of tributylamine and formic acid Scheme 81 Proposed mechanism for photocatalytic reductive intra- (based on McErlean’s Supporting Information) were used, and intermolecular hydroacylation of olefins77 the ketone products were further reduced to form ketyl radicals, which dimerized, forming pinacol-type products (Scheme 80, a). The authors also conducted a one-pot intra- 8 Acyl Chlorides as a Source of Acyl Radicals

molecular cyclization–intermolecular radical–olefin addi- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tion reaction, which afforded the two- and three-compo- Acyl chlorides are versatile intermediates and have been nent coupling products in 29% and 24% yields, respectively widely used as electrophilic acylating reagents in organic (Scheme 80, b). synthesis. Their electrophilic property can be reversed by a The unique feature of this reaction is the formation of single-electron reduction to generate acyl radicals. An early an acyl radical from the thioester, triggered by the genera- example of the formation of an acyl radical intermediate tion of an aryl radical. The idea was inspired by the work of from an acyl chloride was reported by van der Kerk et al. in Crich and Yao.78 It is proposed that reductive quenching of 1957 using triphenyltin hydride.80 Under their conditions, III*/II 56 the excited *Ir(ppy)3 (E1/2 = +0.31 V vs SCE) by tributyl- triphenyltin chloride and benzaldehyde were formed. A ox 61 amine (triethylamine: E1/2 = +0.83 V vs SCE) produces systematic study of the reaction between triphenyltin hy- II – III/II the tributylamine radical cation 81.1 and Ir (ppy)3 (E1/2 dride and benzoyl chloride was conducted by Kuivila in = –2.19 V vs SCE) (Scheme 81).56 This strongly reducing spe- 1960.81 A mechanism that involved the generation of an cies reduces the iodobenzene moiety of thioester 81.2 (io- acyl radical was further demonstrated by Kuivila in 1966.82 The formation of an acyl radical from an acyl chloride via

SET with SmI2 was reported by Kagan et al. in 1981, and the

Syn thesis A. Banerjee et al. Review acyl radical was further reduced to an acyl anion under Anilides with different N-protecting groups such as benzyl, their reaction conditions.83 Only recently, photoredox catal- acyl, and tosyl were competent, delivering the products in ysis was used for acyl radical formation from acyl chlo- 67–70% yields. Aryl-ester-linked 1,7-enynes were also via- rides.84 In 2017, Xu et al. reported the first protocol to con- ble substrates. vert a benzoyl chloride into a benzoyl radical, which then R4 R4 reacted with 1,7-enynes to form fused pyran derivatives R3 O fac-Ir(ppy)3 (5.00 mol%) 84a O 2,6-lutidine (5.00 equiv) O (Scheme 82). The reaction starts with excitation of fac- + R3 R1 Cl X X MeCN (0.100 M) R1 R2 Ir(ppy) by a blue LED and then the excited fac-*Ir(ppy) Blue LED, N2, r.t., 12 h Me 3 3 Me R2 O IV/III* 56 (E1/2 = –1.73 V vs SCE) is involved in single-electron re- 5.00 equiv 1.00 equiv 1 2 3 4 84b X = N, O; R = aryl; R = alkyl, Ac, Ts; R = halogen, CF3, CN; R = aryl, heteroaryl duction of a benzoyl chloride (Ep = –1.02 V vs SCE) form- IV Ph Ph Ph ing fac-Ir (ppy)3 and benzoyl radical 82.2. The benzoyl radical then attacks the carbon–carbon double bond of 82.3 to O O O N N N Me Me Me afford an alkyl radical intermediate 82.4, which undergoes Me Me Me O O O MeO F3C radical cyclization with the alkyne triple bond to form a vi- 90% 55% 89% nyl radical intermediate 82.5. Oxidation of the vinyl radical S IV Ph Ph intermediate by fac-Ir (ppy)3 gives a vinyl cation species 82.6. The acyl carbonyl oxygen then attacks the vinyl cation O O O N N O Ph Me Ph Ts Ph carbon center to form an oxonium ion 82.7, which is then Me Me Me O O O deprotonated to give the desired product 82.8. 63% 70% 50%

Ph Ph Scheme 83 Photocatalytic synthesis of fused pyran derivatives from O fac-Ir(ppy)3 (5.00 mol%) benzoyl chlorides and 1,7-enynes84a O 2,6-lutidine (5.00 equiv) O Cl + N N MeCN (0.100 M) Me Blue LED, N , r.t., 12 h Me Me Me 2 O 5.00 equiv 1.00 equiv In the same year, Xu et al. extended the scope of the re- O Ph action to substrates without an alkyne motif (Scheme 84b Cl O 84). In this reaction, the α-carbonyl radical intermediate N O 82.1 Me Me 84.4, generated from the reaction of N-phenylmethacryl- – III O – Cl *Ir (ppy)3 amide (84.3) and the acyl radical 84.2, undergoes intramo- SET 82.8 lecular cyclization to form intermediate 84.5, which is oxi- Ph 82.2 base – H+ IV O dized by Ir then deprotonated to give a 3,3-dialkyl 2-oxin- Ph N dole derivative. The reaction scope is similar to that Me Me O described in Xu’s previous report (Scheme 83).84a 82.3 IV III N Ph Ir (ppy)3 Ir (ppy)3 Me Me Acyl radicals formed from acyl chlorides can add direct- O O 82.7 ly to alkynes. In 2017, Tang et al. synthesized a diverse O N SET Me Me group of 3-acylspirotrienones via ipso-carboacylation of N- (p-methoxy aryl)propiolamides with acyl chlorides.84c The 82.4 Ph Ph Me Me p-methoxy group on the arene ring is critical to formation

O O of the desired products. The reaction conditions worked O N O N 82.5Me 82.6 Me well with benzoyl chlorides bearing alkyl, methoxy, and Scheme 82 Proposed catalytic cycle for the photocatalytic synthesis of halogen substituents and thiophenecarbonyl chloride, af-

fused pyran derivatives from benzoyl chlorides and 1,7-enynes. Adapted fording the desired products in 60–86% yields (Scheme 85). This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. with permission from ref 84a. Copyright (2017) American Chemical So- N-(p-Methoxyaryl)propiolamides containing a benzyl, 2-io- ciety dobenzyl acyl or allylic groups on the nitrogen atom were tolerated, providing the 3-acylspirotrienones in 69–73% In terms of the acyl chloride substrate scope (Scheme yields. In terms of the alkynyl substituents (R4), pentyl,

83), both electron-deficient (e.g., CF3) and electron-rich thiophene, pyridine, naphthalene, and arenes bearing alkyl,

(e.g., OMe and Me) substituted benzoyl chlorides coupled to methoxy, acyl, CF3, or halogen groups were compatible and afford the desired products in 55–90% yields. Enyne sub- afforded the desired products in 57–88% yields. Mechanisti- strates with alkynyl 3-thiophene and arenes bearing halo- cally, the authors proposed that after the initial photocata- gen, methyl, and methoxy substituents were tolerated and lytic acyl radical formation followed by a two-step tandem formed the desired fused pyran derivatives in 63–92% yields acyl radical-alkyne coupling and radical cyclization, a cyclic (Scheme 83). However, alkynyl alkyl substituents such as t- radical species 85.1 is generated. An 18O-labeling experi- butyl and cyclopropyl groups gave only a trace amount of ment suggests that 85.1 is attacked by an exogenous H2O the desired products. The reaction also tolerates substitu- molecule with assistance from 2,6-lutidine to give a radical ents such as Cl, CN, and CF3 on the arene ring of anilides.

Syn thesis A. Banerjee et al. Review

R3 R4 O fac-Ir(ppy) (5.00 mol%) fac-Ir(ppy)3 (5.00 mol%) O R4 3 O Me 2,6-lutidine (5.00 equiv) O 2,6-lutidine (5.00 equiv) O 3 OMe 1 Cl R + H2O (2.00 equiv) R O R1 MeCN (0.100 M) N R1 2 R1 Cl N R 3 MeCN (0.100 M) N Blue LED, N2, r.t., 12 h O O N R O 3 Me R2 Blue LED, N2, r.t., 12 h R2 R R2 2.00 equiv 1.00 equiv 2.00 equiv 1.00 equiv 1 2 3 R = alkyl, MeO, halogen; R = alkyl, Bn, Ph. R = alkyl, halogen, alkoxide R1 = aryl, heteroaryl; R2 = alkyl, Bn, allyl, Ac; R3 = alkyl, halogen, alkoxide Mechanism O R4 = alkyl, phenyl, naphthalenyl, thiophenyl, pyridinyl F O O O Ph Cl Ph Ph Ph O 84.1 S O O Ph O Ph III *Ir (ppy)3 N N N O O O 84.2 SET Me Me 55% 73% 70% O N N O Me O O O Me Me Ph N Ph n-C5H11 84.3 Me O Ph O Ph O Ph O IrIV(ppy) IrIII(ppy) 84.7 N N N 3 3 O O O O Me OMe Me Me Ph N 61% 61% 57% SET O Me Me base – H+ Proposed Mechanism 84.4 O Ph O Ph photocatalytic 18 aroyl radical formation Ph OMe Ph O O O Me Me N aroyl radical addition N O O 85.1 Me 85.4 Ph N Ph N and radical cyclization Me Me Me 18 O O H2 O 2,6-lutidine IV Ir III 84.5 84.6 Ir O Ph O Ph Scope 18OH Ph Ph 18OH O Me O Me O Me OMe Cl N N N N N O 85.2– MeO O 85.3 Me Me Me Me Me O Me O O 84c 95% 76% 66% Scheme 85 Visible-light-mediated ipso-carboacylation of alkynes MeO

O Me O Me Cl O Me R3 N N 3 O fac-Ir(ppy) (2.00 mol%) O R Ph Me N 2 3 O O Me R 2,6-lutidine (2.00 equiv) Cl O 1 R1 R + MeCN (0.100 M), 100 °C 74% 74% 90% O O 5 W blue LED light O O R2 2.00 equiv 1.00 equiv Scheme 84 Photocatalytic formation of 2-oxindoles from acyl chlo- R1 = alkyl, MeO, halogen; R2 = alkyl, Ph, halogen, alkoxide, Ac; R3 = alkyl, alkoxide, aryl, heteroaryl 84b rides O Ph F O Ph O Ph S

O O O O O O anion intermediate 85.2. Removal of the methoxy group 81% 65% 71% gives 85.3, which is then oxidized by IrIV to afford the de- F sired product 85.4 (Scheme 85). O Ph O Ph In 2018, Tang et al. further expanded this type of acyl O radical chemistry to the synthesis of 3-acylcoumarins O O Me O O Br 85 O O Br (Scheme 86). Although thiophenecarbonyl chloride and 88% 72% 73% benzoyl chlorides bearing methyl, methoxy, and halogen Scheme 86 Photocatalytic synthesis of 3-acylcoumarins via cascade substituents were well tolerated, alkyl, vinyl, and electron- difunctionalization/cyclization of alkynoates and acyl chlorides85 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. deficient (e.g., p-O2NC6H4) acyl chlorides failed to produce the desired products. Aryl 3-phenylpropiolates possessing 36 methyl, halogen, methoxy, Ac and CF3 groups at the p-posi- Itoh’s (Scheme 22) methods involve the formation of a 5- tion of the phenoxy ring underwent the reaction smoothly, exo-trig cyclic intermediate, which is distinct from the tran- affording the products in 68% to 80% yields. With respect to sition-metal-catalyzed acyl radical addition reported by the scope of alkynyl substituents, arenes bearing electron- Wu86 and Wang87 in which a 6-endo-trig cyclization process donating and electron-withdrawing groups were compati- was proposed. ble under the reaction conditions. The proposed reaction mechanism is depicted in Scheme 87. Once the radical intermediate 87.4 is formed, it 9 Acyl Silanes as a Source of Acyl Radicals undergoes an intramolecular 5-exo-trig cyclization followed by oxidation, giving the cationic species 87.6. 1,2-Es- The first isolation of acyl silanes was reported by Brook ter migration leads to 87.7, which upon deprotonation af- in 1957.88 Acyl silanes are often regarded as unusual car- fords the desired product 87.8. Notably, both Tang’s85 and bonyl compounds as a result of the unique feature of an sp2

Syn thesis A. Banerjee et al. Review

O Ph O O O PC COOMe Ph Me COOMe Ph Cl Me TMS + COOMe solvent, light, time O 87.1 COOMe O O Me Eox = +1.46 1.00 equiv Ph III *Ir (ppy)3 –1 87.2 SET 87.8 E1/2 */ Ph EntryPC Solvent Light Yield [%] V vs SCE base – H+ Me 1 TBADT (2.00 mol%) +2.44 MeCN/H2O 5:1 310 nm 72 2 TBADT (2.00 mol%) – MeCN/H2O 5:1 366 nm 52 3 Acr+–Mes (10.0 mol%) +2.06 MeOH 410 nm 81 O O O Ph 2+ 87.3 4 Ru(bpz)3 +1.30 MeCN/H2O 5:1 450 nm n.d. Ph + IV III Ir (ppy)3 Ir (ppy)3 O Ph O O Me O O O 87.7 W Me O Ph PC O O O SET R TMS PC* monooxometalate O O 1,2-ester migration R EWG n 87.4 88.1 88.7 ( Bu4N)4[W10O32] TBADT O Ph O Ph SET H+ Me Ph Me Ph Me O O O O O O + SET R EWG R TMS 87.5 87.6 88.2 88.6 Me Me PC1– Scheme 87 Proposed mechanism for the photocatalytic 3-acylcouma- EWG rin synthesis85 O 88.4 O N Me R EWG R + 88.3 88.5 Acr –Mes carbon that is bonded to both a silicon and oxygen atom.89 Scheme 88 Optimization and reaction mechanism of the photocata- In 1969, Brook and Duff reported that photolysis of acyl lytic hydroacylation using acylTMS as an acyl radical source92 silanes led to the formation of acyl radical intermediates via Norrish type I cleavage of the acyl–silicon bond.90 Electro- red chemical oxidation of acyl silanes leading to the formation Mes (E1/2 = –0.57 V vs SCE), the reduction potential of of acyl radicals was described extensively by Keiji and which is within reach of that of the carbon radical interme- 91 red Yoshida between 1986 and 1992. Application of acyl sila- diate 88.5 (E1/2 ≈ –0.63 V vs SCE). The photocatalytic con- nes in the formation of acyl radicals under photocatalytic ditions operate under a different wavelength of light, mak- conditions was described by Fagnoni et al. in 2017 (Scheme ing it suitable for a range of alkene substrates such as di- 88).92 Acyl- and benzoyltrimethylsilanes (acylTMS and ben- methyl maleate, electron-poor styrenes and acrylonitrile ox zoylTMS) have higher oxidation potentials (E1/2 = +1.26 to (Scheme 89). +1.51 V vs SCE)92 than most of the common transition-met- III*/II Method A: Method B: al photocatalysts such as fac-Ir(ppy)3 (E1/2 = +0.31 V vs O TBADT (2.00 mol%) 56 2+ II*/I 93 O Acr+–Mes (10.0 mol%) SCE) and Ru(bpy)3 (E1/2 = +0.77 V vs SCE). Thus, pho- 2 EWG R2 1.20 equiv acylTMS R 1.50 equiv acylTMS R1 EWG MeCN/H O R1 TMS 2 tocatalysts with stronger oxidizing power are needed to ox- 1.00 equiv (5:1, 0.100 M) MeOH (0.100 M) 310 nm light 410 nm light idize acylTMSs to acyl radicals. Fagnoni et al. discovered R1 = alkyl. R2 = ester, amide, anhydride, CN, alkyl that photoexcited tetrabutylammonium decatungstate O O O 94 A: 73% O A: 16% A: trace (TBADT) and 9-mesityl-10-methylacridinium tetrafluo- B: 23% H13C6 COOMe B: 31% Me B: 75% + 95 COOMe roborate (Acr -Mes) (Scheme 88) could be used to enable CN O the acylation of electron-deficient alkenes. The authors O CN O CN A: trace H13C6 O A: 61% A:63% B: 78% proposed that the excited photocatalyst oxidizes an ac- Me CN B: 55% N Me COOEt B: – ylTMS (88.1) to an acylTMS radical cation 88.2, which then Ph O Me Me Me

loses the TMS group to form a nucleophilic acyl radical Scheme 89 Photocatalytic hydroacylation using acylTMS as an acyl This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 88.3. The formation of the acyl radical was supported by radical source92 their TEMPO trap experiments. The alkyl radical intermediate 88.5 formed by the addition of the acyl radical to alkene 10 Conclusions and Future Outlook 88.4 accepts an electron from the reduced photocatalyst to give a carbon anion 88.6, which is then protonated to form the final product 88.7. Photoredox catalysis has emerged as a powerful tool in Regeneration of the TBADT catalyst through oxidation organic synthesis and has revolutionized how chemists by the carbon radical intermediate was reported by Fag- tackle difficult bond-forming challenges. In this review, we noni.96 Although the absorption spectrum of TBDAT is not have provided an overview of the development of acyl radi- in the visible light region, it overlaps with the spectrum of cal chemistry under photocatalytic conditions. The unique sunlight, supporting this catalyst’s capacity as a ‘window- reactivity of photoredox catalysts offers unprecedentedly ledge’ catalyst. For the Acr+-Mes-catalyzed reaction, *Acr+- mild reaction conditions for the generation of versatile acyl Mes oxidizes the acylTMS to form an acyl radical and Acr•- radicals from a wide range of precursors including aldehydes, α-ketocarboxylic acids, carboxylic acids and anhy-

Syn thesis A. Banerjee et al. Review

drides, acyl thioesters, acyl chlorides, and acyl silanes. The (13) (a) Wang, H.; Guo, L.-N.; Duan, X.-H. Adv. Synth. Catal. 2013, mild conditions also enable the reactions of acyl radicals 355, 2222. (b) Chaubey, N. R.; Singh, K. N. Tetrahedron Lett. with a diverse set of coupling partners to construct molecu- 2017, 58, 2347. (c) Meng, M.; Wang, G.; Yang, L.; Cheng, K.; Qi, C. lar architectures that are otherwise difficult to prepare. Adv. Synth. Catal. 2018, 360, 1218. (14) Wu, X.-F. Chem. Eur. J. 2015, 21, 12252. Since the use of photoredox catalysis in acyl radical chemis- (15) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. try only began in 2013 and is still in its infancy, we antici- 2013, 113, 5322. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. pate that more innovative transformations involving acyl Rev. 2016, 116, 10035. (c) Shaw, M. H.; Twilton, J.; MacMillan, D. radical intermediates will continue to emerge in the near W. C. J. Org. Chem. 2016, 81, 6898. 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