Aldehydes: magnificent acyl equivalents for direct acylation

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Kumar, P., Dutta, S., Kumar, S., Bahadur, V., Van der Eycken, E. V., Vimaleswaran, K. S., Parmar, V. S. and Singh, B. K. (2020) Aldehydes: magnificent acyl equivalents for direct acylation. Organic & Biomolecular Chemistry, 18 (40). ISSN 1477-0520 doi: https://doi.org/10.1039/D0OB01458C Available at http://centaur.reading.ac.uk/93413/

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Received 00th January 20xx, Accepted 00th January 20xx Aldehydes: magnificent acyl equivalents for direct acylation DOI: 10.1039/x0xx00000x Prashant Kumar*,a,b Sriparna Dutta,b Sandeep Kumar,b Vijay Bahadur,a,b Erik V. Van der Eycken,c,d Karani S Vimaleswaran,e Virinder S. Parmarf and Brajendra K. Singh*b

From the viewpoint of meeting the current Green Chemistry challenges in chemical synthesis, there is a need to disseminate how the cocktail of acylation and activation can play a pivotal role in affording bioactive acylated products comprising of Manuscript substituted ketone motifs in fewer reaction steps, with higher atom-economy and improved selectivity. In recent years, a significant number of articles employing the title compounds “aldehydes” as magnificent acylation surrogates have been developed which are less toxic and widely applicable. This review sheds light on their use for selective acylation of arenes, heteroarenes and alkyls (sp3, sp2 and sp) C-H bonds by proficient utilization of C-H activation strategy. Critical insights on selective acylation of diverse moieties for the synthesis of bioactive compounds are presented in this review that will enable the academic as well as the industrial researchers to understand the mechanistic aspects involved and fruitfully employ these strategies in designing novel molecules. 1. Introduction Crafts acylation reaction include requirement of harsh

reaction conditions and super stoichiometric amounts of Accepted The concise forging of substituted ketone motifs by means of Lewis acids, low regioselectivity and the formation of direct functionalization using C-H activation strategies unwanted regioisomers.6,7 Although other alternative presents the incredible state of the art in synthetic organic methods have been established over the years comprising of chemistry. Ketones are commonly used ubiquitous structural the oxidation of alcohols,8,9 Grignard/Barbier reaction units for developing pharmaceuticals, dyes, agrochemicals, followed by oxidation,10 and reaction of Grignard reagents electronic materials and natural products. These are the with nitriles,10f these methods do not match the current Green fundamental building blocks of various bioactive molecules Chemistry requirements due to issues related to safety and and drugs such as tiaprofenic acid and ketoprofen which are economy. used as anti-photoallergic agents1 and nonsteroidal anti- Chemistry inflammatory drugs,2 fenofibrate that is used as the classical Transition metal-catalyzed oxidative cross-coupling reactions lipid regulating agent3, benzbromarone (BBR) which is for the direct functionalization of C-H bonds with high atom- employed as a uricosuric agent4, and mebendazole that works efficiency have emerged as attractive, efficient and as a broad-spectrum human anthelmintic agent.5 Over the straightforward strategies for access to desirable molecules course of time, structural diversity of the disubstituted ketone from simple reaction substrates without any pre-modification

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. moieties has rapidly expanded as evident from the literature or pre-functionalization, thereby increasing the efficacy of the reports. However, the practical challenges associated with the anticipated transformations. Therefore, in recent years these conventional methodologies employed for the synthesis of cross-coupling strategies have been extensively explored for these significant motifs have in turn engaged the researchers the direct synthesis of keto compounds by means of selective in exploration of improved methods of synthesis. Some of the acylation of the starting materials. These approaches are inherent drawbacks associated with the classical Friedel- found to be highly advantageous over classical methods used Biomolecular for the acylation of alkyl, aryl or heteroaryls leading to the & formation of desirable acylated compounds because of fewer a. Department of Chemistry, SRM University Delhi-NCR, Sonepat Haryana-131029, India reaction steps, higher atom-economy, improved selectivity b. Department of Chemistry, University of Delhi, Delhi-110007, India and non-requirement of pre-functionalization of the starting c. Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 materials. For direct acylation by following the C-H activation Leuven, Belgium d. Peoples’ Friendship University of Russia, (RUDN University) Miklukho-Maklaya, approach, several reagents including aldehydes, benzyl street 6, Moscow, 117198, Russia alcohols, -keto acids, acyl chlorides, etc. have been explored e. Hugh Sinclair Unit of Human Nutrition, School of Chemistry, Food and Pharmacy,

University of Reading, UK extensively.11-14 Amongst these acylating surrogates, Organic f. Department of Chemistry and Environmental Science, Medgar Evers College, The City University of New York, 1638 Bedford Avenue, Brooklyn, NY 11225, USA aldehydes (aliphatic and aromatic) have received profound

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attention because of their high stability, less toxicity, ease of routes provided better alternatives to anhydrides,View Article Online acyl availability, broad substrate scope and low cost. halides, -ketoacids and other acylatingDOI: agents. 10.1039/D0OB01458C32-34 Ideally, it is well known that green chemistry helps in achieving In fact, aldehydes consist of an important class of molecules reduction of waste at source by redesigning existing processes that are found extensively in nature. Amongst the aldehydes, at the molecular level. These acylation reactions add to the benzaldehyde is one of the most important motifs, which is credentials of green chemistry. A major breakthrough in the widely used in food industry as an ingredient in cherry and use of aldehydes as acylating agents was achieved when other natural fruity flavours. Naturally, aldehyde motifs are Cheng et al. in 2009 reported the first direct oxidative present in peach, black tea, bitter almond, and apricot acylation of a C-H bond applying aromatic aldehydes as acyl kernel.15 Benzaldehyde has been reported to act as an anti- 35 tumour agent for various kinds of tumours occurring in equivalents in the presence of a Pd-catalyst. During humans16 and mice.17 The mechanism for the anti-tumour mechanistic investigation of the radical induced acylation

behaviour of benzaldehyde for cell growth inhibition has been reactions, it was postulated that the aldehyde moiety gets Manuscript well established using human NHIK 3025 cells.18 Aldehydes converted first into an acyl radical (Fig. 2) which then can be formed endogenously by amine oxidases, combines to give the corresponding acylated product.

carbohydrate or ascorbate autoxidation, lipid peroxidation, O O myeloperoxidase-catalyzed metabolic activation, Oxidant R H R carbohydrate metabolism or by cytochrome P-450s, etc.19,20 Acyl radical In the year 1946, the first review21, which was published by Fig. 2 Acyl radical formation from the aldehydes. Lloyd N. Fergusoy from the University of California, on the synthesis of aromatic aldehydes, covered essential The use of benzaldehydes in radical mediated as well as Accepted information pertaining to both the direct as well as indirect oxidative cross-coupling reactions was reviewed by Xiao-Feng method for the introduction of the formyl (CHO) group into Wu in 2015.33 This mini-review sheds light on recent work in the aromatic nucleus. It was highlighted in this review that transition metal catalysed acylation of aryls, Gattermann and Koch22 for the first time prepared aromatic heteroaryls/heteroarenes. Thereafter, in 2016, Kim and co- aldehydes via reaction between benzene and its derivatives, workers published a review summarizing the recent progress CO and HCl, using anhydrous AlCl3 as a catalyst. Thereafter, in oxidative and decarboxylative transition metal-catalysed this protocol was modified further by Gattermann23 himself, acylation reactions by C-H activation.34

where he used cyanide instead of CO and produced aldimine Chemistry 2. Scope of Review hydrochloride as an intermediate that was hydrolysed to the aldehyde. In due course, several other methods were There is a need to disseminate how wondrously the aldehyde established for aldehyde synthesis. Also, meanwhile attempts moieties are employed in various acylation reactions using C- were made towards utilizing aldehydes for their H activation and how they succumb to provide a better transformation into valuable compounds. For instance, it was substitute of the irritating and toxic anhydrides, acyl halides

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. found that benzaldehyde could react with pyruvate and get and other acylating reagents. Although there are several transformed into a chiral compound (R)-phenylacetylcarbinol reviews on C-H bonds activation and transition metal- [(R)-PAC] with the help of pyruvate decarboxylase (PDC) catalysed reactions, yet, to the best of our knowledge, there enzyme (Fig. 1).24, 25 is no single review that throws light on the use of aldehydes as magnificent acylation surrogates compiling the acylation of OH O O O 3 2 PDC CH3 arenes, heteroarenes and alkyls (sp , sp and sp) C-H bonds Biomolecular H CO2 H O O CH3 resulting in the synthesis of valuable C-X (X=C, O, N) bonds by proficient use of C-H activation. This review presents some of & Fig. 1 Transformation of benzaldehyde and pyruvate into (R)-phenylacetylcarbinol using pyruvate decarboxylase. the exciting discoveries accomplished during the past few Henceforth, aldehydes were employed as starting materials in years (2012 to 2020) in the development of novel catalytic important organic reactions such as addition, condensation, protocols, shedding light on some of the latest synthetic tools hydrogenation, coupling, etc.26-31 Over the course of time, including flow chemistry and photochemical methodologies. aldehydes were also employed in radical acylation and It includes a comprehensive discussion on the mechanistic oxidative acylation reactions that result in the direct aspects that will enable the researchers to think creatively and Organic regioselective formation of new C-C and C-N bonds. These work in this exciting area. This review focusses on using

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greener tools and strategies, given that chemical waste has a 10 min and a 1.1 kH/kD value was observed (SchemeView 1B Article). Other Online disastrous impact on human health as well as on the deuterium-labelling control experimentsDOI: suggested 10.1039/D0OB01458C the rapid environment and eco-systems. and reversible metalation-proto(deutero)demetalation before the cross-coupling reaction. This also suggested that 3. Aldehydes in acylation reactions addition of the aldehyde to the cyclo-rhodated intermediate 3.1. Acylation of arenes is involved in the rate-limiting step of this conversion. A In 2012, Kim and his team described the Rh-catalyzed possible reaction mechanism is depicted in Scheme 2.

regioselective acylation of secondary benzamides using H/D O

aromatic aldehydes, which on subsequent intramolecular D O D3 N H/D D 36 N HO cyclization afforded 3-hydroxyisoindolin-1-ones (Scheme 1). H D D Authors have synthesized 21 derivatives of 3- D H hydroxyisoindolin-1-one by reacting several differently Rh(I) Manuscript O Rh(III) Ag2CO3 O substituted benzamides with aldehydes. Benzaldehydes H/D O N H/D D N H 4 D5 N Rh (III) having electron-withdrawing groups such as NO2, CF3, D3 Rh(I) B A D O COOMe, CN, etc. delivered the 3-hydroxyisoindolin-1-ones in H high yields. On the other hand, aldehydes carrying the PhCHO (III)Rh O

electron-releasing OMe group displayed inferior reactivity. H/D O N H D4 Benzamides having electron-releasing groups delivered high H/D O H/D D3 N C N Rh (V) yields in comparison to those bearing electron-withdrawing D H 3 Rh(I) D O groups. H/D O O Accepted F D D N H/D HD O 3 A [Cp*RhCl2]2 (5 mol %) Rh (III) O AgSbF (20 mol %) 6 O O 3 R3 Ag2CO3 (300 mol %) R2 N R N 1 R2 H o H R THF (0.3 M), 150 C R1 HO H/D O E 20 examples, 30-83% H/D N 1 D3 H R = Ph, 4-CF3Ph, 4-CO2MePh, 4-NO2Ph, 4-COMePh, 4-CNPh, 4-FPh, 4-ClPh, 4-BrPh, 4-OMePh, -naphtyl O R2= 5-Ph, 5-Cl, 4-OMe, 4-OBn, 4-Cl, 3-OMe, 3-F, Rh(III) G 1,3-dioxolyl, etc. H R3= i-Pr Scheme 2: Plausible reaction mechanism of the Rh-catalyzed regioselective sp2 C-H acylation B O process for the secondary benzamides with aryl aldehydes. Chemistry D O H O O i H R D iPr H Pr N N N H H4/D4 (i) H In 2013, Zhang et al. developed a Pd-catalysed protocol for the standard R H H D D condition OH synthesis of keto-carboxylic acids through an aryl amide D H 10 min R = 4-(MeO C)Ph 2 kH/kD = 1.1 directed C-H functionalization approach. The reaction (27% D)

standard H/D proceeded by oxidative coupling between aryl amides and D O O (10% D) O conditions D iPr D N A-C aldehydes using TBHP as oxidant and resulted in imino

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. N H/D H X R (ii) 20 h D D D OH carboxylic acids, which on subsequent treatment with HCl X = H, X = D D D R = 4-(MeO C)Ph 37 2 D/H solution gave keto carboxylic acids. The reactions condition A: X = H, THF (8% D) progressed through benzamide directed o-acylation followed condition B: X = D, THF CO2Me condition C: X = D, THF-d8 by ring closing and opening to give keto-carboxylic acids. Both benzamides as well as aldehydes bearing electron-releasing

(50% D) Biomolecular D O H/D O groups and electron-withdrawing groups were compatible for D iPr standard H/D N condition D (iii) H N the reaction irrespective of the positions of the functional & H (21% D) D D without aldehyde within 2h D H/D D groups. The authors prepared 19 imino carboxylic acid D (50% D) derivatives in 46-84% yield and five keto-carboxylic acid Scheme 1: Rh-catalyzed regioselective sp2 C-H acylation of secondary benzamides using aryl aldehydes with intramolecular cyclization and mechanistic studies. derivatives in 50-80% yield (Scheme 3). To probe the catalytic reaction pathway for this Two closely related studies were disclosed by Patel et al. and transformation, authors carried out intermolecular kinetic Wu et al. in 2013 using Pd(II) catalyst and TBHP oxidant for isotope experiment by treating equimolar amounts of direct o-acylation of 2-arylbenzothiazoles and 2- deuterated benzamide and simple benzamide with methyl Organic arylbenzoxazoles. In the first study,38 the authors reacted terephthalaldehydate under standard reaction conditions for

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R1 benzothiazoles or benzoxazoles with aldehydes using View Article Online H O R2 N DOI: R10.1039/D0OB01458C2 Pd(OAc)2 as catalyst and TBHP as oxidant in toluene as solvent O Pd(OAc)2 , TBHP N

1 + toluene, 5-6 h (Scheme 4). A set of 38 o-acylated benzothiazoles and H R X 3 X R o R3 X= S & O 110 C benzoxazoles were prepared in moderate to good yields. The X= S & O

developed method was robust and adequate for diverse 38 examples, 40-84% X=O X= S azoles and aldehydes. The method seemed to be insensitive R1= Ph, 4-MePh, 4-PhPh, 3-ClPh R1= Ph, 4-OMEPh, 4-OBuPh, 4-MePH, 4-PhPh, 4-ClPh, R2= H, 5-Me 4-CO MePh, 4-NO Ph, 3-FPh, 3-ClPh, 3-NO Ph, 2-ClPh, to the electronic behaviour of the substituents present either 2 2 2 R3= 4-Me, 4-OMe, 4-Cl 3,4-OMePh, 2,6-ClPh, 4-Cl-3-NO2Ph, naphthyl, furanyl, on azoles or aldehydes. thiophenyl, ethylbenzene R2= H O R3= H, 4-Me, 4-OMe, 4-O-t-Bu, 4-t-Bu, 4-Cl, 6-Cl, 5-F, 5-Br O R3 OH Scheme 4: Pd(II)-catalyzed direct ortho-acylation of 2-arylbenzothiazoles and O R2 N 3 R2 H Pd(OAc) , TBHP N R 2-arylbenzoxazoles. 1 2 R H BF .Et O 39 H 3 2 1 o R In a second study, the authors reported the o-acylation of 2-

DMSO/dioxane, 130 C Manuscript arylbenzoxazoles using aldehydes as coupling partner in the 19 examples, 46-84%

R1= Ph, 4-OMePh, 4-MePh, 4-ClPh, presence of Pd(OAc)2 catalyst, PPh3 as ligand and TBHP as 3,4,5-OMePh R2= H, 4-OMe, 4-F, 4-Br, 4-Cl, 2-OMe, oxidant (Scheme 5). 24 ortho-acylated benzoxazole 2-Me, 3-OMe, 3-Cl derivatives were obtained in 37-85% yield. Benzothiazole and R3= OMe, OBn, O-i-Pr, O-t-Bu benzo[h]quinoline were efficiently coupled with p- O O O R3 chlorobenzaldehyde giving the respective ortho-acylated OH N 2 R2 H R R1 H Pd(OAc)2, TBHP O products in 83% and 96% yield after 8 h at refluxed . H BF3 Et2O o 1 temperature. Unfortunately, 2-(3-

DMSO/dioxane, 130 C R Accepted then conc. HCl (aq), reflux 5 examples, 50-81% methylphenyl)benzimidazole was unable to give the acylated R1= Ph, 4-ClPh, 4-OMePh product under the optimized reaction conditions. R2= 4-Cl, 4-OMe Scheme 3: Pd-catalyzed synthesis of imino carboxylic acids and keto- Remarkably, 2-arylbenzoxazoles having substituents on the carboxylic acids via aryl amide directed C-H activation reaction. meta-position of the benzene ring exhibited high regioselectivity and acylation achieved at the less crowded ortho-C-H bond of the directing group. The steric hindrance at the ortho-position of aromatic aldehydes influenced the reaction efficiency and resulted in a lower yield of the Chemistry corresponding acylated products. Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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A R1 Ph CHO 2 R O O 3 2 3 N R Pd(OAc)2 (5 mol%) R R C + TBHP (6 equiv) N N R1 O O PPh3 (10 mol%) PhCl, reflux, 8 h O O N 24 examples, 37-85% Pd(OAc)2 1 R = H, 3-OMe, 3,4-OMe, 4-Me, 4-Cl, 4-Br, 4-F, Manuscript 2-OMe, 2-Cl, 2,4-Cl, 2-Br, 4-Cl HOAc R2= H, 7-Me, 5-Cl R3= H, 2-Me, 3-Me, 3-OMe, 3-F, 3-Cl, 4-F AcOH O

B Cl N O Pd O L = Ph3PO N Pd(OAc)2 (5 mol%) AcO L TBHP (6 equiv) N A H O TBHP X + O PPh3 (10 mol%) Pd L Cl Me PhCl, reflux, 8 h N L OAc X= S & NH Ph tBuO O O X B Me Ph H X = S; 83% tBuOH Accepted X = NH; 0% t Ph PO tBuOH PPh3 + BuOOH 3 +

O Pd(OAc)2 (5 mol%) TBHP (6 equiv) H N + PPh3 (10 mol%) O N Cl PhCl, reflux, 8 h

Cl 96% Scheme 5: Pd-catalyzed ortho-acylation of 2-arylbenzoxazoles/ 2-arylbenzothiazoles/2-arylbenzimdazoles and plausible reaction mechanism.

For both the reactions similar reaction pathway was experiments were carried out. The observations suggested

suggested as presented in Scheme 5C. Mechanism starts with that the N-Boc hydrazone moiety is acting as directing group. Chemistry cyclopalladation of the 2-arylbenzoxazole or 2- The rate of the acylation reaction was found to be significantly arylbenzothiazole to give intermediate A. In the second step, faster than that of the hydrolysis step. Scheme 6B also the in-situ generated acyl radical reacts with intermediate A outlines the mechanism of this transformation. to form either reactive PdIV or dimeric PdIII intermediate B. In the last step, reductive elimination resulted o-acylated

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. derivatives of 2-arylbenzoxazole and redeveloped PdII salt to maintain the catalytic cycle.

Kim and his group in 2013 reported the first catalytic acylation protocol to synthesize 1,2-diacylbenzenes from N-Boc 40

hydrazones. This method involves the Pd(II)-catalysed Biomolecular tandem regioselective acylation of N-Boc hydrazones and in-

situ dissociation of the directing N-Boc hydrazone group in the & presence of TBHP as oxidant delivering 1,2-diacylbenzenes (Scheme 6). This approach was set up not only for various aldehydes but also for several acetophenones and benzophenone N-Boc hydrazones. Unfortunately, aliphatic and heterocyclic aryl aldehydes were unable to give the coupling products with this catalytic system. To acquire Organic greater understanding of the reaction pathway, various

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3 R Boc R3 furan-2-carbaldehyde delivered the products in 86% and 66% A O View Article Online NH Pd(OAc) (10 mol%) N 2 DOI: 10.1039/D0OB01458C 2 TBHP (4 equiv) O yield, respectively. Cyclohexanecarbaldehyde and H R1 R R2 o O H DCM, 70 C, 10 h propionaldehyde also reacted smoothly to give the R1 O corresponding reaction products in 59% and 64% yield,

1 O O R = Ph, 4-OMePh, 4-OBnPh, 4-MePh, 4-CF3Ph, respectively. The synthesized acylated azobenzenes were O O 4-FPh, 4-ClPh, 3-OMePh, 2-OMePh, 3,5- ClPh, MeO 2-F-4-OMePh, -naphthyl converted into the indazoles using Zn/NH4Cl/MeOH as 2 R = 4-CF3, 4-OMe, 4-Br, 4-Cl, 4-F, 4-NO2, 5-Me, 5-F, 6-F reducing system at room temperature in just 5 min (Scheme R3= Me, Ph 7). 35% 36%

2 R2 R B Me Boc Me Boc O Pd(OAc) N NH N 2 N NH N N 1 N R H TBHP, DCE, N2 O R2 TBHP O R2 H R1 Manuscript Pd(OAc)2 Ph Me 23 examples, 41-86% AcOH R1= Ph, 4-OMePh, 4-MePh, 4-BrPh, 4-ClPh, O 4-FPh, 4-CNPh, 4-NO Ph, 4-PhPh, 3-OMePh, Zn-NH Cl O 2 4 Me Boc 2-MePh, 2-ClPh, 2-FPh, naphtyl, 3-NH2-4-ClPh, MeOH, rt, 5 min Me Boc Ph NH 3,5-OMePh, furanyl, cyclohexyl, propyl N NH R2= H, Me, OMe, Cl N N [Pd] N R2 [Pdll] O R2 Ph A B R1 O t O BuO 23 examples, 92-99%

H Scheme 7: Pd-catalyzed azo group directed acylation of symmetrically Accepted substituted azobenzenes with aldehydes. tBuOH Scheme 6: Pd(II)-catalyzed direct regioselective acylation of N-Boc hydrazones and plausible reaction mechanism. Meanwhile, Sharma et al. reported a Pd-catalyzed oxidative o- acylation of triflamide-protected benzylamines using aliphatic In 2013, Li et al. reported an azo-group directed selective and aromatic aldehydes via C-H activation strategy. It was acylation of symmetrically substituted azobenzenes by observed that benzylamines having triflamide as directing aldehydes involving a Pd-catalysed C-H activation method.41 group delivered o-acyl-N-benzyltriflamides with high Using optimized reaction conditions, the scope of various regioselectivity applying Pd(OAc)2 as catalyst and TBHP as azobenzenes and aldehydes was explored using Pd(OAc)2 and

ideal oxidant. They used AcOH as an additive and the reactions Chemistry TBHP. Aromatic aldehydes containing strong electron- were carried out in the binary solvent system MeCN/DMF withdrawing groups such as CN, NO at the para-position of 2 (1:1) (Scheme 8A).42 the aryl ring provided higher yields than those containing electron-releasing groups (Me, OMe) at the para-position. Reactions of azobenzene with -naphthaldehyde as well as Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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TfHN TfHN A Pd(OAc)2 (7.5 mol %) O O TBHP (4 equiv) AcOH (50 mol%) 1 H R1 R R2 R2 MeCN/DMF (1:1) 100 oC, 40 h 20 examples, 16-75% TfHN Me O 1 R = Ph, 4-OMePh, 4-MePh, 4-CO2MePh, 4-CF3Ph, Manuscript 4-FPh, 4-ClPh, 2-OMePh, 3-OMePh, 4-OHPh, OMe 2-F-4-OMePh, -naphtyl, pentyl, i-Pr, 16% R2= 2-OMe, 2-Me, 3-Me, 2,4-OMe, 2-F, 2-Cl

B NHTf C

NHTf TfHN TfHN O OH R 1. MeI, K2CO3, acetone Pd(OAc)2 60 oC, 10 h, 84% O AcOH Cyclopalladation o 2. LiAlH4, THF, 80 C Reductive 12 h, 56% Elimination NTf AcOH Accepted Pd NTf A Me N Pd OAc Oxidation O R O B tBuO O O 59

R H R tBuOH Scheme 8: (A) Pd-catalyzed oxidative acylation of N-benzyltriflamides with aldehdyes via C-H activation; (B) plausible reaction mechanism; (C) transformation of triflamides. Chemistry The substrate scope examination revealed that electron poor aromatic aldehydes were less reactive in comparison to electron rich aromatic aldehydes. In order to examine a plausible reaction mechanism for this transformation, the radical scavenger, ascorbic acid, was added in a dose-

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. dependent manner and it was found that the reaction proceeds via a radical pathway as shown in Scheme 8B. They have also established that o-acyl-N-benzyltriflamides are effective synthetic precursors for the construction of the analgesic drug nefopam and analogous (Scheme 8C).

Novàk and co-workers reported a Pd-catalysed cross- Biomolecular

dehydrogenative coupling of anilides with aromatic aldehydes & using mild reaction conditions for the selective o-acylation of anilides (Scheme 9).43 Organic

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ARTICLE Organic & Biomolecular Chemistry

O 44 A O Pd(OAc)2 (5 mol %) TBHP as oxidant (Scheme 10A). All the usedView substrates Article Online SDS (5 mol %) Me NH O DOI: 10.1039/D0OB01458C O HN Me TFA (26 mol%) delivered the anticipated products in moderate to good yields R1 H R1 R2 R2 TBHP (2 equiv), H2O, rt to 40 oC, 24 h regardless the nature of the substituents. Noticeably, 2-aryl- 30 examples, 32-98% O 1,2,3-triazole and benzaldehyde both containing strong Me NH O R1= Ph, 4-BrPh, 3-BrPh, 4-ClPh, 3-ClPh, electron withdrawing groups such as COOMe (on triazole) and 2-ClPh, 4-FPh, 3-FPh, 2-FPh, 4-MePh, 4-OMePh, 3-NO2Ph, thiophenyl, styrenyl CN (on benzaldehyde) gave the corresponding product in 82% R2= H, 2-Me, 3-Me, 4-Me, 4-i-Pr, 2-OMe, 3-OMe, 3-F, 3-Cl, 3-Br 38% yield. However, the highest yield (85%) was obtained in two B O cases: 1) when unsubstituted 2-aryl-1,2,3-triazole was treated NH O with benzaldehdye and 2) coupling of benzaldehyde bearing a Ph strong withdrawing cyano (CN) group with 2-aryl-1,2,3-

monomeric path dimeric path triazole having strong electron donating methoxy (OMe) Pd(OAc)2 O group. Interestingly, high regioselectivity was observed with Manuscript O O Ph NH Ph O O meta-substituted 2-aryl-1,2,3-triazole and acylation at the Pd O HN O HN O Pd O para-position with respect to the meta-substituent was

O H HN Pd N achieved instead of ortho-position due to steric hindrance. O reductive O S b 6 elimination [TS2m] O reductive A Pd [TS2b] N N Pd(OAc) (10 mol%) N N elimination H 2 N O O O N N TBHP (1 equiv) O O Ph 1 O S1 R O O 1 2 DCE, 15 h, 80 oC R2 HN Pd R H R O Pd carbopalladation [TS1] Ph O O O 26 examples, 25-85% O H HN Pd N Accepted O O S5m R1= Ph, 4-t-BuPh, 2-OMePh, 2,5-OMePh, S5b O 4-CF Ph, 3-BrPh, 2-BrPh, 4-FPh, 2-FPh, O Pd 3 O 2-ClPh, 2,4-ClPh, 4-CNPh, -naphtyl, Ph H O methyl, ethyl, ethylbenzene, styrenyl, O N R2= H, 4-CO Me, 5-Cl, 5-Me, 5-OMe, 5-CF O O 2 3 HN Pd S Ph O H 2 O B Pd N N O N N N -2H O -H O N O HN Pd O O dimerization S3m S3b Pd(OAc) O O 2 TBHP AcOH Ph H Ph

Scheme 9: Pd-catalyzed cross-dehydrogenative coupling between anilides Chemistry and benzaldehydes, and proposed reaction mechanism. N N Ac N O N N Pd o Remarkably, this reaction was accomplished at 25-40 C N OAc 2 Pd R temperature under aqueous conditions in 24 h. Utilization of O the surfactant dodecyl sulphate (SDS) helped to upturn the A B

t solubility of the reaction substrates in water, and O BuO O

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. trifluoroacetic acid (TFA) accelerated the reaction in water. R R H

The presence of electron releasing or electron withdrawing tBuOH groups on the anilide does not affect the reaction outcome Scheme 10: Pd-catalyzed acylation of 2-aryl-1,2,3-triazole scaffolds with differently substituted aryl and alkyl aldehydes and resulted in high yield of the products. Aromatic aldehydes and plausible reaction mechanism. with weak electron-withdrawing groups (F, Cl, Br etc.)

provided higher product yield, than those containing electron- Based on the available reports and observations, the authors Biomolecular releasing groups (Me, OMe). 3-nitrobenzaldehdye delivered designed a plausible reaction mechanism that starts with the the desired product in just 39% yield. In order to support the formation of a five membered cyclopalladation intermediate & hypothesis regarding the probable reaction mechanism, A between 2-aryl-1,2,3-triazole and the Pd-catalyst. authors have performed quantum mechanical density Subsequently, the generated benzoyl radical reacts with functional calculations, which suggested the preference of intermediate A resulting in conversion of Pd(II) to the dimeric bimetallic catalysis over a monomeric route (Scheme 9B). Pd(III) or Pd(IV) complex B. Lastly, this complex B undergoes reductive elimination leading to the acylated product and In 2014, Kuang and co-workers described the acylation of 2- Pd(II) get regenerated for the subsequent cycle (Scheme 10B). aryl-1,2,3-triazole scaffolds with differently substituted aryl Organic

and alkyl aldehydes using Pd(OAc)2 as effective catalyst and

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Organic and Biomolecular Chemistry ARTICLE

In August 2014, Kuang et al. reported the first example of a prepared with 56-85% yield. The reactionView proceeded Article Online Pd-catalysed direct ortho-acylation of 2-benzyl-1,2,3-triazoles successfully with substrates having electronDOI: 10.1039/D0OB01458C donating or by aldehydes via C-H bond activation in the presence of electron withdrawing groups. However, 2-benzyl-1,2,3- 45 Pd(OAc)2 as catalyst and TBHP as oxidant. Using the triazole bearing a nitro group at the para-position was not optimized reaction conditions, the substrate scope with found to be reactive and no acylated product was obtained respect to aldehydes as effective acyl source, and 2-benzyl- (Scheme 11). The reaction was found to progress following 1,2,3-triazoles was explored, and 26 derivatives were the reaction pathway as shown by Kuang et al. (Scheme 10B).

R1 O

O N Pd(OAc)2 (10 mol%) N TBHP (2.0 equiv) N 2 N R 2 1 + o R R H N DCE, 80 C, 16 h N

26 examples, 56-85%

R1= Ph, 2-OMePh, 2,5-OMePh, 2-FPh, 4-FPh, Manuscript

4-ClPh, 3-BrPh, 4-CNPh, 2-NO2Ph, 4-i-Pr, furanyl, styrenyl, ethylbenzene, ethyl R2= H, 5-Me, 3-Me, 5-OMe, 5-F, 5-Cl,

4,5-ClPh, 5-CF3, 5-NO2 Scheme 11: Pd-catalyzed direct ortho-acylation of 2-benzyl-1,2,3-triazoles.

3 A R Sun et al. in 2014 introduced azoxy compounds for selective R3 Pd(TFA) O O 2 acylation. The authors developed an interesting approach for O (10 mol%) N N N N TBHP the selective ortho-acylation of azoxybenzenes using various R1 H O DCE, 60 oC

2 Accepted aromatic, heteroaromatic and aliphatic aldehydes in the R 1 R2 R 46 presence of Pd(TFA)2 as catalyst and TBHP as oxidant. They 18 examples, 23-91% 1 prepared 19 different mono-acylated azoxybenzenes with 23- R = Ph, 4-CNPh, 4-NO2Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-OMePh, 3,5-OMePh, 4-MePh, 3-MePh, 87% yield in 24 h at 60 oC. The presence of mild electron- 2-MePh, propyl, furanyl, thiophenyl, R2= H, 4-F, 4-Cl, 4-Me, 4-OMePh withdrawing groups (F, Cl, Br) at the para-position of the R3= H, 4-F, 4-Cl, 4-Me, 4-OMe benzaldehydes positively affected the reaction giving higher B O N O yields of the mono-acylated derivatives. However, strong N N O N electron-withdrawing groups (CN, NO2) had a reverse effect

resulting in very poor yields of the corresponding products. Pd(TFA)

2 Chemistry Unfortunately, other electron-withdrawing groups like CF3 Cyclopalladation AcOH and CO2Me were not suitable for this transformation as no Reductive desired products were obtained. Besides the presence of two Elimination O N N ortho-C-H bonds, the reaction afforded exclusively the mono- O N Pd N acylation in the ring directly attached to the N=O group TFA (Scheme 12A). The ortho-acylation product was converted Pd Oxidation A Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. TFA into the indazole analogue by a reduction process. The R O t BuO O reaction was found to progress through a free radical pathway B O R H (Scheme 12B). R tBuOH Scheme 12: Regioselective ortho-acylation of azoxybenzenes with aldehydes using Pd(TFA)2 and plausible reaction mechanism.

In 2014, Patel and his team established a strategy for the Biomolecular regioselective ortho sp2 C-H acylation of 3,5-diarylisoxazole.47 From four sp2 C-H bonds and one interior sp2 C-H bond, the & functionalization occurred at one of the ortho C-H bonds near

to the N-atom in the presence of Pd(OAc)2 as catalyst and TBHP as oxidant(Scheme 13A). Organic

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ARTICLE Organic & Biomolecular Chemistry

A O 2 extended to substituted 2,3-diarylquinoxalinesView Article Online with R2 R Pd(OAc)2, DCE DOI: 10.1039/D0OB01458C + Ph benzaldehydes and good yield of the desired products were R1 H Ph TBHP, 110 oC N N 1 O O 8-12 h R O achieved (Scheme 14).

13 examples, 39-73% 1 R3 R R1= Ph, 4-MePh, 4-t-BuPh, 4-OMePh, H O 3-ClPh, 4PhPh, 4-CO2MePh, 2,6-ClPh, O R2 3 N Pd(OAc) (5 mol%) R2 R -naphtyl, thiophenyl, furanyl 2 N Toluene : DCE (1:1) R2= H, 5-Me, 5-OMe R1 H + N TBHP (1.5 equiv) B H N 110 oC, 8 h R3 H R3 Ph 23-examples, 11-82% N O Ph O X R1= H, 4-MePh, 4-OMePh, 4-OBuPh, 4-PhPh,

4-ClPh, 4-NO2Ph, 4-CO2MePh, 3-ClPh, 3-FPh, Ph Reductive H Elimination 3-NO2Ph, 3.4-OMePh, -naphtyl, thiophenyl 2 PdX2 R = H, 6,7-Cl, 6-Me, 6-Cl O X = counter R3= H, 4-Me, 4-Br, 3-Me-4-OMe N anion or OAc Scheme 14: Cross dehydrogenative coupling for directed mono ortho-acylation Manuscript Pd (I) of sp2 C-H bonds of 2,3-diarylquinoxaline. X O B Cyclopalladation Ph N Oxidative Ph O Methyl and chloro substituted unsymmetrical 2,3- H Ph Addition diarylquinoxalines after reaction with benzaldehyde provided O HX N N inseparable mono-acylated products in a ratio of 5:4 and 5:3, O O O Pd (I) Ph respectively. Furthermore, when the reaction with 2,3- Ph N O A X t diarylquinoxaline having two electron-releasing groups (-Me BuO O tBuOH

and -OMe) in one of the aryl ring was performed, mono ortho- Accepted Ph H Scheme 13: Pd-catalyzed selective N-directed ortho-acylation of 3,5-diarylisoxazoleacylated products were obtained in a 6.7:1 ratio, revealing the and proposed reaction mechanism. favoured oxidative palladation at the more electron rich aryl Authors reported 13 acylated products with high ring. However, in the presence of bromine in one of the aryl regioselectivity in 39-73% yield at 110 oC after 8-12 h in rings, ortho-acylation was accomplished at the unsubstituted dichloroethane (DCE) as solvent. The reaction progressed aryl ring, resulting in only one product and reconfirming the smoothly with the applied substrates and was found favoured oxidative palladation of more electron rich aryl ring compatible with all kinds of functional groups present on the (Scheme 14). aldehydes. Nevertheless, the electron-withdrawing groups

The reaction conditions applied in regioselective acylation of Chemistry such as o-NO2, p-Cl, m-F in 3-aryl ring of 3,5-diarylisoxazole suppressed the product formation completely under these azobenzenes (Scheme 15) were effectively installed by Wu reaction conditions. The reaction mechanism was not and co-workers in 2015 during the acylation of azoxybenzenes o thoroughly probed but expected to proceed as outlined in by aldehydes using Pd(OAc)2 as catalyst at 80 C in the 49 Scheme 13B. presence of TBHP as oxidant (Scheme 15A). The authors have prepared a library of derivatives using differently In continuation of their work on selective N-directed acylation

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. substituted azoxybenzenes and aryl/alkyl aldehydes. reactions, Patel and co-workers reported a cross However, in comparison to Sun’s protocol46, aliphatic dehydrogenative coupling methodology for the selective aldehydes gave inferior yields and heterocyclic aldehydes mono ortho-acylation of the sp2 C-H bond of 2,3- could not be applied for this transformation, which shows the diarylquinoxalines using aromatic aldehydes.48 The authors significance of the reaction temperature. The authors also developed a small library of 23 derivatives employing performed some control experiments to investigate the Biomolecular Pd(OAc) , TBHP and toluene:DCE (1:1) at 110 oC. Various 2 reaction mechanism. When the reaction was carried out in the

functional groups were well tolerated on the benzaldehyde & presence of the radical scavenger 2,2,6,6- and p-chlorobenzadehyde provided the highest yield (82%). tetramethylpiperidyl-1-oxyl (TEMPO) no acylation product Benzaldehydes bearing strong electron-withdrawing groups was obtained revealing a free radical pathway (Scheme 15B). like p-COOMe, p-NO , m-NO also provided the desired 2 2 The probable reaction route for this conversion is shown in products in good yields. The substrate scope was further Scheme 15C. Organic

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A O O 2 R2 R2 O R Pd(OAc) (5 mol%) N N 2 N N R2 TBHP (4 equiv) R1 H R C DCE, 80 oC, 12 h O O 26 examples, 38-89% N N 1 O R = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CF3Ph, 4-PhPh, 4-MePh, 4-OMePh, 3-ClPh, O 3-MePh, 2-ClPh, 2-CF3Ph, 2-MePh, 2-OMePh, 3,4-MePh, 2,3-OMePh, -naphthyl, cyclohexyl N 2 N Manuscript R = H, 4-OMe, 4-Me, 4-Et, 4-i-Pr, 4-CO2Et, 2-Me, 3-Me, 3,5-Me B O Pd(OAc) O 2 O Pd(OAc)2 (5 mol%) N AcOH N N N DCE, 80 oC, 12 h Ph H O

O Ph O N NR N N O O N O Pd(OAc)2 (5 mol%) Pd TBHP (4 equiv) A N N Pd OAc N Ph H N TEMPO (2 equiv) tBuOH O Ph t DCE, 80 oC, 12 h O BuO B O tBuOOH Ph CHO NR OH

O O Accepted O Pd(OAc)2 (5 mol%) PhCOOH TBHP (4 equiv) N N Ph OH N N DCE, 80 oC, 12 h O

NR= No reaction Ph NR Scheme 15: (A) Regioselective ortho-acylation of azoxybenzenes with aldehydes; (B) Control experiments; (C) plausible reaction mechanism.

In 2015 Xiao et al., successfully carried out the acylation of the for the acylation of the aryl ring of 2-phenylpyridines, aryl ring of acetophenone O-methyl oxime with aromatic diphenyldiazenes, aromatic azo-compounds and other aryl aldehydes using almost similar reaction conditions as was ketone oximes with aromatic aldehydes (Scheme 16A-D). The 50

used by Novàk’s and co-workers as given in Scheme 9. In this reactions proceeded effectively in all these cases and Chemistry case reactions were carried out at 50 oC for 12 h and the electron-releasing or electron-withdrawing groups were targeted products were achieved in 53-80% yields. The compatible under standard reaction conditions. authors extended the application of the reaction conditions

OMe A R2 N MeO Pd(OAc)2 (5 mol %) C N Ph N O Pd(OAc)2 (5 mol %) N O TBHP (2 equiv) Ph O SDS (5 mol%) O N TBHP (2 equiv) Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. R3 R1 SDS (5 mol%) H R1 N H2O (0.6 mL) H 2 R 50 oC, 12 h H2O (0.6 mL) o 3 50 C, 12 h R1 R R1 14 examples, 53-78% 8 examples, 53-75% R1= Ph, 4-MePh, 4-OMePh, 4-FPh, 4-ClPh, R1= H, 4-Me, 4-OMe, 4-F, 4-Cl, 4-BrPh, 4-t-BuPh, 2-ClPh, -naphtyl 4-Br, 2-Cl, 3-Me 2 R = H, Me, C2H5 R3= H, Me, OMe, Cl B R2 D Biomolecular R2 Pd(OAc) (5 mol %) O NOCH3 O 2 O TBHP (2 equiv) NOCH3 Pd(OAc) (5 mol %) & 2 N TBHP (2 equiv) SDS (5 mol%) H O H SDS (5 mol%) H2O (0.6 mL) 50 oC, 12 h H2O (0.6 mL) R1 N 50 oC, 12 h 82% R1 12 examples, 52-80% Pd(OAc) (5 mol %) O 2 N TBHP (2 equiv) O R1= H, 4-Me- 4-OMe, 4-F, 4-Cl, SDS (5 mol%) H 4-Br, 4-t-Bu, 2-Cl, 3-Me N H2O (0.6 mL) 2 R = Me, OMe, Cl 50 oC, 12 h

51% Organic Scheme 16: Pd-catalyzed acylation of aryl ring (A) acetophenone O-methyl oximes; (B) 2-phenylpyridines; (C) diphenyldiazenes; (D) aryl ketone oxime and aza phenanthrene with aromatic aldehydes.

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Yi’s group in 2015 described the synthesis of ortho- the use of K2CO3 as base and PPh3 as additive in acylphenols by performing an oxidative C-H coupling reaction chlorobenzene solvent for the smooth transformation at 110 between phenols and aldehydes using the cationic ruthenium oC (Scheme 17). Interestingly, the coupling of phenols with +  hydride complex [(C6H6)(PCy3)(CO) RuH] BF4 as an effective -unsaturated aldehydes under the optimized reaction catalyst in the absence of metal oxidant.51 The reaction conditions resulted in flavonoids. The authors prepared 20

progressed significantly with the applied phenols and flavonoid derivatives successfully with 23-88% yield having Manuscript aldehydes comprising electron donating and electron various functional groups. The chemoselectivity of the withdrawing groups, and resulted in the formation of 26 developed protocol was explored by treating estrone with ortho-acylphenol derivatives in 35-78% yield. Besides the cyclohexanecarbaldehyde and 4-chlorobenzaldehdye and the cationic ruthenium hydride complex, the reaction involved corresponding coupling products were obtained in a 1:2 ratio.

A OH OH O B O [(C H )(PCy )(CO) RuH]+BF OH R4 6 6 3 4 R1 H O O R3 1 [(C H )(PCy )(CO) RuH]+BF H R R2 R2 6 6 3 4 o 1 PPh3, K2CO3, PhCl, 110 C 4 R R1 R 8-20 h R2 PPh3, K2CO3, PhCl 2 o R 18 examples, 43-78% 110-130 C, 12-24 h Accepted 3 R 20 examples, 23-88% R1= Ph, 4-MePh, 4-FPh, 4-ClPh, 1 4-CF3Ph, 2-BrPh, Et, n-Pr, i-Bu, R = 7-OMe cyclohexyl, CH(Me)Ph R2= H, Me, n-hexyl R2= 4-OMe, 4,6-Me R3= H, Ph, n-Pr, Et, 4-FPh MeO O R2= H, R3= n-Pr; 40% R4= H, Ph OH OH O O R3 R2= Me, R3= Ph; 46% O [(C H )(PCy )(CO) RuH]+BF R2= Me, R3= Ph; 42% 6 6 3 4 1 R 2 3 1 R = n-hexyl, R =Ph; 59% H R o 53% R2 PPh3, K2CO3, PhCl, 110 C 8-20 h 6 examples, 33-61% 4 R 2 3 4 O R O R3 R = H, R = H, R = n-Pr; 71% R2= Me, R3= H, R4= Ph; 60% 1 R = Ph, 4-FPh, Et, cyclohexyl, R2= H, R3= Ph, R4= Ph; 56% OH 2 3-cyclohexenyl, CH(Me)Ph R R = Ph; 35% R = Cy; 38% Chemistry

Scheme 17: (A) Synthesis of 2-acylphenol via oxidative C-H coupling reaction of phenols with aldehydes; (B) Coupling between phenols and -unsaturated aldehydes.

In the same year Wu et al. reported a study for the direct to probe either the reaction was following an ionic pathway ortho-acylation of 2-phenoxypyridines with aldehydes to or proceeding via a radical pathway. The results of produce a series of novel aryl ketones in the presence of experiments strongly supported the radical pathway. In

Pd(OAc)2 as catalyst, TBHP as oxidant and chlorobenzene as addition to the above studies, some other control Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. solvent (Scheme 18).52 In order to gain an insight into the experiments were also performed by carrying out the reaction reaction mechanism, authors performed intramolecular and between 2-phenoxypyridine palladacycle (A) with different intermolecular kinetic isotope effect studies. The results of benzaldehydes in the presence and absence of TBHP. Based experiments showed that the ortho C-H bond cleavage of 2- on all these experiments, a plausible mechanism was phenoxypyridines does not participate in the rate determining proposed as shown in Scheme 18B. The authors also Biomolecular steps of the reaction. The binding of 2-phenoxypyridines with demonstrated the synthetic utility of this protocol by

the palladium ion was considered as the crucial rate- synthesizing (2-hydroxyphenyl)(phenyl)methanones and 1- & determining step for the acylation. Furthermore, the effect of hydroxy-9H-fluoren-9-ones. various radical scavengers on the reactivity was determined Organic

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A B

O N O O N N N O Pd(OAc)2 (10 mol%) PhCl R1 R2 + 1 2 O ll O H R TBHP (2 equiv), 140 oC R Pd (OAc)2 20 h O 32 examples, 3-94% R1 R1= Ph, 4-MePh, 4-OMePh, 4-NO Ph, 4-CF Ph, 2 3 Manuscript OAc O 4-AcPh, 4-FPh, 4-ClPh, 4-BrPh, 4-IPh, 2-FPh, Pdlll or lVL 3-FPh, 3-ClPh, 3-BrPh, 3-CHOPh, 3,5-MePh, O R1 Ar 2,5-MePh, 3,5-OMePh, 5-OMePh, 3,4,5-OMePh, C N ll N Pd (OA -naphthyl lll or lV Pd L c)2 R2= H, 5-Me, 5-OMe, 5-NO , 5-F, 5-Cl, 5-Br, 5-I O 2 O OAc

D A

O O N O O N O O N O R1

N Pdlll or lV(OAc) L O AcOH 2 O O 94% 1 90% 27% O R Accepted

O TBHP B H R1 Scheme 18: Direct ortho-acylation of 2-phenoxypyridines with aldehydes and proposed reaction mechanism.

Triphathi et al. in 2015 reported a metal-free one pot radical Heterocyclic aldehydes such as furan-2-carboxyaldehyde and

approach for the cross coupling between aryl diazonium thiophen-2-carboxyaldedye provided the respective products Chemistry tetrafluoroborates and aldehydes to access the synthesis of in 65% and 88% yield. Bulkier aromatic aldehydes, - diaryl ketones.53 A library of 20 derivatives was established by naphthaldehyde and - naphthaldehyde provided the 89% coupling differently substituted aromatic aldehydes with and 79% yield, respectively. Aryl diazonium tetrafluoroborate various derivatives of aryl diazonium tetrafluoroborate using having electron-withdrawing (F, Br) groups resulted higher di-tert-butylperoxide (DTBP) as a radical initiator. The product yields than that of containing electron-releasing (Me)

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. presence of electron-releasing (Me, OMe) groups as well as group (Scheme 19A). Based on experimental data and electron-withdrawing (F, Cl, NO2, COMe) groups on aromatic literature precedents, authors described a plausible reaction aldehydes was well tolerated under the developed conditions mechanism for this transformation (Scheme 19B). and afforded the corresponding products in 72-95% yield. Biomolecular & Organic

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O A O DTBP, DCE R -N BF 1 2 R1 H 2 2 4 R R 80 oC, 0.5-1 h 20 examples, 65-95%

R1 = Ph, 4-OMePh, 4-MePh, 4-FPh, 4-ClPh,

2-MePh, 3-NO2Ph, 3-COMePh, 3,4-OMePh, thionphenyl, furanyl, -naphthyl, -naphthyl R2 = Ph, 4-FPh, 4-MePh, 2-MePh, 4-BrPh Manuscript B HF F

F F tBu O B F tBu O B F H F F

N2BF4

F BF BF3 F t t 4 Bu O B F Bu O BF3 F N2 Accepted

O O O tBu OH

H

t tBu O O tBu 2 Bu O

Scheme 19: (A) Metal-free cross coupling between aryl diazonium tetrafluoroborates and aldehydes to the synthesis of diaryl ketones; (B) plausible reaction mechanism.

In early 2016, Jiao and co-workers reported the N- applied for benzo[h]quinolone, 1-phenylpyrazole, 2-

hydroxyphthalimide (NHPI) and palladium co-catalyzed phenylpyridine and 2-phenoxypyridine and the corresponding Chemistry oxidative acylation of acetophenone o-methyl oxime using targeted products were acquired in moderate to good yields aldehydes via selective C-H functionalization. In this protocol (Scheme 20B). Unfortunately, azobenzene and acetanilide molecular oxygen was used as terminal oxidant for C-H provided inferior yields of the acylated products and phenyl acylation.54 A wide range of o-methyl oximes and aldehydes N,N-dimethylcarbamate was found to be unreactive under (alkyl/aryl) was explored and various derivatives were these reaction conditions. The removal of the directing group

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. prepared bearing electron withdrawing and releasing groups using HCl/dioxane and subsequent intramolecular aldolization at 80 oC within 24 h in 1,4-dioxane as solvent (Scheme 20A). in the presence of NaOH/DMSO converted the oxime ether The developed acylation reaction conditions were also into the isoindoline (Scheme 20C). Biomolecular & Organic

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OMe B A C MeO R2 N R= Ph N Pd(OAc)2 (5 mol %) O O NHPI (20 mol%) O Me DG = R2 1 N O Me 3 o R N Ph R1 H R 1,4-dioxane, 80 C, 24 h 3 N N O N R , , N O2 (1atm) , H ZrCl4 NaBH4 Me 88% 55% 60% O 33 examples, 32-90% 11% THF, rt R1= Ph, 4-MePh, 4-t-BuPh, 4-ClPh, 4-CF Ph, 4-CNPh, 3-FPh, 3 O Ph OMe i N OH 3-ClPh, 3,4,5-OMePh, 3-Br-4-OMePh, -naphthyl, N Pr N 85% Manuscript N O naphthyl, cyclopropyl, cyclohexyl, pentyl, 1-pentenyl, N N 2-methyl-1-propeneyl Me O Me2N O 1) HCl, dioxane R2= Me, Ph, C H , C H N HO 2 5 6 13 , N , 50 oC NHPI 3 R = 4-OMe, 4-t-Bu, 4-n-Bu, 4-CF3, 4-NO2, 4-Br, 4-Cl 27% 2) NaOH, DMSO, 0% rt OMe OMe OMe 91% N N Me N O N 51% O O O O

, 90% 60% 58% 82%

Scheme 20: NHPI and palladium co-catalyzed aryl C-H bond aerobic oxidative acylation in presence of various directing group with aryl/alkyl aldehydes and Accepted conversion of acylation product into isoindoline and 3-hydroxy-3-phenylindanone.

Zhao and Jiang in 2016 reported a proficient method for the gain insight into the reaction mechanism. The reaction selective acylation of 1,4-disubstituted 1,2,3-triazoles between 4-phenyl-1-(p-tolyl)-1H-1,2,3-triazole and applying the 1,2,3-triazole moiety as directing group using benzaldehyde in the presence of the free radical scavenger aromatic aldehydes as acyl transfer agent in presence of Pd- TEMPO gave only traces of the desirable compound catalyst (Scheme 21A).55 The best reaction conditions were demonstrating a radical pathway. Moreover, the

used to prepare 27 derivatives in 55-92% yield after 24 h of intermolecular kinetic isotope effect (kH/kD) was also reaction at 120 oC. Reaction proceeded with almost equal determined and was found to be 6.3, suggesting that the cl Chemistry efficacy in case of aldehydes as well as 1,4-disubstituted 1,2,3- cleavage of the C-H bond may be the rate-limiting step triazoles. However, aldehydes with strong electron (Scheme 21B). Based on outcomes of these experiments, a

withdrawing groups (NO2, MeS=O) afforded relatively lower plausible reaction mechanism was proposed as outlined in yields. Further the authors carried out several experiments to Scheme 21C. Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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R3 R1 A O N N Pd(OAc) (10 mol%) N N O R2 2 R2 N TBHP (4 equiv), X-Phos 3 N R 1 H DCE, 120 oC, 24 h R C R1 27 examples, 55-92% O N N R1= 2-MePh, 2-OMePh, 2-ClPh, 3-MePh, 3-OMePh, N N N 3-BrPh, 3-ClPh, 3-NO2Ph, 4-MePh, 4-OMePh,

N Manuscript 4-BrPh, 4-ClPh, 4-SOMePh, 4-i-PrPh R2= 2-Cl, 2-I, 2-Me, 3-Me, 3-Br, 4-Me, 4-OMe, 4-NO Me 2 PdllL R3= 2-Cl, 2-Me, 3-Me Me B Ph AcOH O (i) Radical capture N O TEMPO N Me N N (0.6 mmol) Me N N L N Ph H N N optimized condition 1 Pd N O R N Me N L Me Pd Ph (ii) Kinetic isotope effect O A N t N N BuO O N B O Accepted N N 1 Pd(OAc) ,TBHP R H O 2 R1 X-Phos, DCE tBuOH Me Ph D Ph H o Me D 120 C, 8 h O D N N N N N D N D

D D Me D D Me

Scheme 21: (A) Regioselective acylation of 1,4-disubstituted 1,2,3-triazoles with aromatic aldehydes; (B) control experiments; (C) plausible reaction mechanism.

In contradiction of directing-group assisted direct acylation, in with pyridinecarboxaldehyde and thiophenecarboxaldehyde. Chemistry 2016, Suchand and Satyanarayan described an Furthermore, product formation could not be observed with environmentally benign protocol for the Pd-catalysed direct bromo arene implying that the more reactive iodo arenes are acylation of an aryl system starting from simple and necessary for the achievement of this transformation. To commercially available iodo arenes and aldehydes (alkyl/aryl), further demonstrate the synthetic utility of this newly leading to the production of aryl-aryl and alkyl-aryl ketones developed protocol, it was extended to the synthesis of 56

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. (Scheme 22A). In total, 69 derivatives could be prepared in benzofuranones by selective reduction of the keto group with

45-89 % yield using of Pd(OAc)2 as catalyst, Ag2O as additive NaBH4, followed by in-situ intramolecular nucleophilic attack and 70% aqueous solution of TBHP as oxidant after 12 h at 120 of the hydroxyl group to the ester group of selected acylated oC, revealing a broad substrate scope and generality of the compound to afford the corresponding benzofuranones developed method. However, p-nitrobenzaldehyde could not (Scheme 22B). This approach was also used for the

result in the corresponding product but reaction was found to preparation of the antispasmodic pitofenone a combined Biomolecular be compatible with m-nitroiodobenzene. The reaction was drug in Spasmalon. Pitofenone was successfully prepared in favorable with furan-2-carboxaldehyde, but was unsuccessful just two steps using this protocol (Scheme 22C). & Organic

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A R2 Pd(OAc) (5 mol%) COOMe O I 2 C CHO Ag2O (1.2 equiv) (1)Pd(OAc)2 (5 mol%) O 2 R1 H R O Ag2O (1.2 equiv) 70% TBHP in H2O (5 equiv) COOMe 70% TBHP in H2O (5 equiv) 120 oC, 12 h R1 120 oC, 12 h (2) pipeidine (3 equiv) I O K2CO3 (3 equiv) 67 examples, 42-83% O N DMF, 50 oC, 1 h N Br 1 82%

O O R = Ph, 4-MePh, 4-OMePh, 4-EtPh, 4-BrPh, Manuscript S 4-ClPh, 4-FPh, 4-OHPh, 4-OC3H7Ph, 2-BrPh I Pd(OAc)2 3-OMePh, 3,4-OMePh, benzo[d][1,3]dioxol-2-yl, D O solvent furanyl, i-Pr, i-Bu, cyclohexyl, n-Bu, n-Pr, R1 R2= 2-CO Me, 4-CO Me, 2-CO Et, 2-CO -i-Pr, R 2 2 2 2 R1 Pd(0) 42% 45% 2-CO2-n-Bu, 2-CO2-n-Amyl, 2-CO2NHPh, H,3-Me, 3-OMe, 4-OMe, 3,4-OMe, [1,3]dioxol-5-yl, 3-NO2

B (II) O Pd O CO2Et O NaBH (2 equiv) 1 4 2 (II) R CeCl 7H O (1 equiv) R Pd R 3 2 O o A MeOH, 0 C to rt 12 h 1 O R O TBHP R Accepted R R H 78-95% B Ag2O R= Ph (95%); n-Bu (78%) TEMPO O cyclohexyl (86%) AgI N O R

Scheme 22: (A) Pd-catalyzed direct acylation of iodo arenes with aldehydes (alkyl/aryl) leading to the aryl-aryl and alkyl-aryl ketones; (B) Conversion to benzofuranones by selective reduction of keto group; (C) conversion to pitofenone; (D) plausible reaction mechanism.

To investigate the reaction mechanism, the authors corresponding acylated products in good yields. Next, the anticipated that the reaction may progress through the scope of aldehydes was also investigated by coupling a wide

development of an acyl radical of aldehyde due to TBHP. This range of aliphatic and aromatic aldehydes with 5-bromo-2- Chemistry hypothesis was proven by performing the reaction in the (trifluoromethyl)pyridine and the desired products were presence of TEMPO under standard conditions, as no product obtained in good to excellent yields. A triple catalytic formation was observed whereas the aldehyde radical- activation mechanism was proposed for this transformation trapped ester was obtained in 95% yield. A plausible reaction (Scheme 23B). In the proposed mechanism, the photocatalyst

pathway for this transformation is shown (Scheme 22D). Ir[dF(CF3)ppy]2(dtbbpy)PF6 was excited into *Ir[dF(CF )ppy] (dtbbpy)+ in presence of visible light. The Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. In 2017, Xiahng et al. established a protocol for direct C-H 3 2 excited *Ir(III) affected the oxidation of quinuclidine to form functionalization of aldehyde via photoredox, nickel, and radical cation and reduced Ir(II) complex. The formed radical hydrogen atom transfer catalysis in a synergistic approach.57 cation then participates in hydrogen-atom transfer to This simple and efficient protocol transforms a wide variety of generate the corresponding acyl radical. Subsequently, commercially available aldehydes with aryl or alkyl bromides

oxidative addition of aryl bromide to L Ni(0) species delivers Biomolecular into the desired ketones in excellent yield (Scheme 23A). Aryl n the aryl-Ni(II) species, which is converted into acyl-Ni(III) bromides containing electron-withdrawing groups such as complex. After reductive elimination, the desired ketone & CO2Me, CN, CF3, SO2Me delivered the slightly higher product product is obtained along with Ni(I) species. This is one of the yield in comparison to those containing electron-releasing crucial step where both nickel and photoredox catalytic cycles Me, OMe groups. Monocyclic as well as bicyclic aromatics would simultaneously turn over via single electron transfer were also coupled effectively with tert-butyl-4- from the reduced Ir(II) species to the Ni(I). Lastly, the formylpiperidine-1-carboxylate to furnish the respective quinuclidine catalyst is generated with the help of inorganic products in good to excellent yields. Noticeably, vinyl base via deprotonation of quinuclidinium ion. bromides and alkyl bromides were also delivered the Organic

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A Ir photocatalyst Ni catalyst F O O F3C Br quinuclidine tBu 1 R2 1 2 N R H K CO , dioxane, rt R R tBu 2 3 F N Br 20 h, 34W blue LEDs F Ni N Br 42 examples, 55-93% Ir N R1 = tert-butyl piperidine-1-carboxylate, n-hexyl, n-Pr, Me, N N ethylbenzene, i-Pr, neopentanyl cyclohexyl, Ph, 4-FPh, N 4-OMePh, tetrahydro-2H-pyranyl, cyclopentanyl, cyclopropyl etc. tBu

t F Manuscript R2 = 4-MePh, 4-OMePh, 4-AcPh, 4-CO2MePh, 4-CNPh, 4-CF3Ph, Bu F C 4-SO2MePh, 4-OCF3Ph, 2-CNPh, 3-CNPh, 3-MePh, 5-F-2-MePh, 3 Ni catalyst quinuclidine 2-methoxypyridinyl, 2-fluoropyridinyl, 3-cyanopyridinyl, Ir photocatalyst 5-fluoropyrodinyl, quinolinyl, isoquinolinyl, pyrimidinyl, 2-methylprop-1-enyl, but-2-enyl, 4-(tert-butyl)cyclohex-1-enyl, butyronitrile, tetrahydro-2H-pyranyl, oxetanyl

B O + Br -H

Br LnNiII Ar BocN

N N H LnNio

Nickel catalytic Br Accepted IrII Cycle Organocatalytic Cycle reductant LnNiIII Ar O SET O alkyl SET HAT BocN Photoredox Catalytic Cycle LnNiI Br

O *IrIII IrIII O N oxident H BocN BocN Chemistry Visible light Scheme 23: (A) C-H functionalization of aldehyde via photoredox, nickel, and hydrogen atom transfer catalysis; (B) plausible reaction mechanism.

Newman and co-workers accomplished the direct protocol also afforded benzothiophenes in good yield that intramolecular coupling between organotriflates and showed a non-traditional/conventional disconnection for aldehydes using an innovative catalytic system comprising of acquiring gateway to the synthetic precursor to raloxifene

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Ni0 precatalyst, a phosphine based ligand and a base in 2017 which is a significant estrogen receptor modulator. The most (Scheme 24A).58 This catalytic reaction pathway provided a notable aspect of this protocol was that it lied within the ready access to a relatively large number of ketone-containing premises of sustainable synthesis by not involving the use of compounds and prove to be superior to the conventional any directing group (DG) that prevented waste generation and Friedel-Crafts reaction (FCRs). Unlike the FCRs, it did not pose also eliminated the need for stoichiometric activation or any selectivity or reactivity related complexities. Both intramolecular reactivity. It was anticipated by the authors Biomolecular electron donating, withdrawing and bulkier sterically that the mechanism primarily proceeded through a Heck type & hindered hypothesis- were well tolerated on both the mechanism involving the role of  bond of aldehyde moiety in coupling partners. Interestingly, the aliphatic aldehydes were the insertion-elimination stage. difficult to couple as they invariably lead to the formation of Tishchenko-type side products in presence of TMP. However, as the authors tried to switch to the quinuclidine motif, they successfully managed to obtain desired ketones. Besides,

complex biologically active molecules could also be Organic synthesized and derivatized. It was striking to note that the

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2 2 A 2 R R R View Article Online O DOI:N 10.1039/D0OB01458CN 1 O N Pd(OAc)2 (10 mol%) O R O Ni(cod)2 (10 mol%) 1 TBHP (6 equiv) Triphos (12 mol%) R H N N 1 2 N 1,4-dioxane R3 R3 OTf R R R3 1 o R H 2 120 C, 24 h R1 R TMP (1 equiv) R1 4 0 32 examples, 20-97% R4 R R4 PhMe, 20 h, 110 C O O 36 examples, 0-94% R1 = Ph, 2-MePh, 4-CNPh, 3-FPh, 2,3-OMePh, pyridinyl, 1 thiophenyl, benzothiophenyl, furanyl, 3-hydroxyPh, R = Ph, 4-OMePh, 4-NO2Ph, 4-CF3Ph, 4-AcPh, 2-FPh, indiolyl, 4-ClPh, cyclohexyl, ethylbenzene, n-pentane, 3-FPh, 4-FPh, 2-ClPh, 3-ClPh, 3-BrPh, 4-BrPh, 1-benzylpiperidinyl, tert-butyl 1H-indolyl-1-carboxylate 3,5-MePh, 2,4-MePh, 3,4-OMePh, 3-CHOPh R2 = H, Me, OMe, 6-methoxy-b-naphthyl, etc. R3 = H, Boc, Moc, pivaloyl, acetyl, Bn R2 = Ph, 4-OMePh, 4-COMePh, pyridinyl, 4-CNPh, 4-FPh, etc. R4 = 2-OMe, 3-OMe, 4-OMe, 4-F, 3-F, 2-F, 4-Cl, 4-Br B R2 Scheme 24: Ni-catalyzed direct intramolecular coupling between organotriflates and aldehydes. N N 3 R R2 Manuscript In 2019 Chu et al. reported Pd(II)-catalyzed late stage ortho C- R1 N H bond acylation of anilines with aromatic aldehydes using 3- O N R3 methoxy-2-pyridinyl as removable directing group.59 A wide Pd(OAc)2 2AcO I substrate scope of differently substituted aryl aldehydes and R1 O

N-protected anilines was explored to synthesize 26 R2 PdIII or IV R2 N PdII sol N monoacylated derivatives of aniline using Pd(OAc)2 as catalyst OAc N N and TBHP as oxidant (Scheme 25A). However, in few cases R3 R3 IV R1 II along with monoacylated aniline formation diacylated O Accepted R2 product was observed. Aromatic aldehydes bearing electron- PdIII or IV N OAc O O releasing as well as electron-donating groups reacted TBHP AcOH N R1 R1 H smoothly to give corresponding acylated products in good R3 III yields under optimized reaction conditions. Scope of Scheme 25: (A) Pd(II)-catalyzed late stage ortho C-H bond acylation of anilines with substituted N-protected anilines was determined by coupling aromatic aldehydes; (B) plausible reaction mechanism. In 2020, Panda and his group reported direct o-acylation of N- with benzaldehyde and aniline having electron releasing OMe methoxysulfonamides with aromatic aldehydes in the group provided slightly better result in comparison to anilines presence of Pd(OAc) as catalyst and TBHP as oxidant.60 In this having electron donating F, Cl and Br groups. To elucidate 2 transformation sulfonamide served as directing group. The whether reaction is proceeding through radical pathway or Chemistry scope of various N-methoxysulfonamides was investigated not radical trapping experiments were carried out using BHT with aromatic aldehydes by synthesizing 22 o-acylated (butylated hydroxytoulene), DPE (1,2-diphenylethylene) and derivatives of N-methoxysulfonamides in 31-68% yields TEMPO as free radical quencher. The results of the (Scheme 26A). Aryl aldehydes as well as N- experiments revealed that a radical species could be involved methoxysulfonamides having electron-releasing groups or in reaction. Furthermore, investigation of kinetic isotope electron-withdrawing groups reacted smoothly and delivered Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. effect indicates that the Pd-catalyzed ortho C-H bond cleavage the good yields of corresponding products. However, aliphatic of aniline is not involved in rate-determining steps. On the aldehydes such as heptanal and nonanal yielded the desired basis of the results of these experiments a plausible reaction products in poor yields. Unfortunately, in case of -NO group mechanism was given by authors (Scheme 25A). 2 reaction failed due to the deactivation of the ring and starting material was recovered. Biomolecular To design the reaction mechanism some control experiments & such as deuterium exchange and kinetic isotope effect were carried out (Scheme 26B). Deuterium exchange experiment revealed that the initial cleavage of ortho C-H bond of N- methoxysulfonamide produces aryl-Pd intermediate involving a reversible process. Kinetic isotope effect suggested that intial cleavage of C-H bond is a rate-limiting step. On the basis

of these experiments and literature precedents a plausible Organic reaction mechanism was proposed as shown in scheme 26C.

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O A O Pd(OAc) (10 mol%) O O 2 S O S TBHP (2 equiv) NHOMe NHOMe O 1 1,4-dioxane (2 mL) R H o C O H 100 C, 15 min R2 O R2 R1 S O NHOMe O 20 examples, 28-68% S O 1 NHOMe R = Ph, 4-MePh, 4-ClPh, 4-BrPh, 4-FPh, 4-NO2Ph, 2-BrPh, Me

4-CNPh, 4-CO MePh, -hexyl, -octyl, styrenyl Manuscript 2 n n Ph Me 2 R = H, 4-Me, 4-Et, 4-Cl, 4-Br, 4-OMe, 3,4-OMe, 3,4-Me, Pd(OAc)2

3,4-Cl, 4-NO2,

B Control experiments AcOH a) Deuterium exchange experiment AcOH O O Pd(OAc) (10 mol%) O O 2 S O O S TBHP (2 equiv) O O O NHOMe O S NHOMe S S D2O NHOMe NHOMe 1,4-dioxane (2 mL) NHOMe Me D(H) lV Me H 100 oC, 15 min lll OAc 20 equiv. Me Pd Me Pd 90% recovery Me Pd 2 0.5 mmol O 2 OAc O Ph 7% deuterium inclusion Ph O Ac O b) Kinetic Isotops Effect (KIE) Accepted O O O t O BuO O S S NHOMe NHOMe O O Ph Ph H H 46% tBuOH O Ph 0.25 mmol Pd(OAc)2 (10 mol%) TBHP (2 equiv) Ph H D O 1,4-dioxane (2 mL) D O O 0.75 mmol o O D S 100 C, 15 min D S NHOMe NHOMe kH/ kD = 3.3 O D D D 14% D 0.25 mmol D Ph Chemistry Scheme 26: (A) Pd-catalyzed direct o-acylation of N-methoxysulfonamides with aromatic aldehydes; (B) control experiments; (C) proposed reaction mechanism.

In quest for exploring the efficacy of photoredox catalysis in and 2-bromobenzothiazole could render substantial amount C-H activation, König and team in 2019 designed a of product. Benzaldehyde also permitted the benzoylation of photocatalytic pathway involving Ni based catalyst and bromobenzene and electron rich bromides in good yield. achieved the dual catalytic benzoylation of aryl bromides.61 Additionally, the scope of 4-bromobenzonitrile as the Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. This unique pathway involved the efficient and smart coupling partner was also explored. While most of the amalgamation the concepts of photochemistry (395 nm LED benzaldehydes showed good reactivity including the

as photoirradiation source) and nickel-catalysis Ni(dmbpy)Br2. fluorinated benzaldehydes, yet 4-hydroxybenzaldehyde and The investigation was initiated by targeting the coupling of 4- 4-aminobenzaldehyde could not react to furnish the desired chlorobenzaldehydes and 4-bromobenzonitriles. The results ketone. Based on various computations and experimental Biomolecular of the screening experiment revealed acetone as the optimal studies, a plausible mechanistic pathway was proposed

solvent, Ni(dmbpy)Br2 as the most efficient precatalyst and (Scheme 27B). During the photoredox catalytic cycle, the first &

Na2CO3 as the preferred base. Thereafter, as the scope of the step involved the absorption of photon by benzophenone (BP) reaction was examined, it was found that the electron which led to the generation of a triplet state BP*. This in turn deficient substrates rendered the desired benzophenones in facilitated the abstraction of hydrogen atom from aldehyde, good to excellent yields. In particular, the halogenated ketone leading to the formation of both the acyl radical as well as the moieties were obtained in moderate to good yields. Also the radical BP-H. The acyl radical was trapped by the generated Ni heteroaryl ketones could be synthesized in moderate yield (II) species B formed via the oxidative addition of the Ni(0) (Scheme 27A). Notably, 2-bromo-4-(trifluoromethyl)pyridine complex A into the aryl bromide. The so formed Ni (III) species Organic

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C was anticipated to form benzophenone BP and complex D 3.2. Acylation of alkyls View Article Online via reductive elimination. The catalytic cycle was finally DOI: 10.1039/D0OB01458C 3.2.1. Acylation of sp3 carbons completed through the single electron transfer from BP-H to the Ni(I) bromide D, that furnished Ni(0) complex A and BP Rovis and co-workers (2012) employed a dual-catalysis (ground state). strategy for the asymmetric sp3 -acylation of 1,2,3,4- A Ni(dmbpy)Br tetrahydroisoquinoline using aldehydes as acylating agents. A O 2 O Br Na2CO3 2 chiral N-heterocyclic carbene (NHC) in combination with 1 R R1 R2 R H acetone, 395 nm LED 3+ o photocatalyst [Ru(bpy)3] was used in the presence of m- 8 h, 25 C 27 examples, 40-98% dinitrobenzene (m-DNB) under blue light irradiation.62 Various

1 t R = Ph, 4-CNPh, 4-CO2MePh, 2-CNPh, 4-CF3Ph, 4- BuOPh, aldehydes were reacted with substituted N-aryl-1,2,3,4- t 4-MePh, 4- BuPh, 4-CF3OPh, 3-FPh, 3-CF3Ph, 4-BzOPh 2 t tetrahydroisoquinolines and 16 derivatives were prepared in R = Ph, 4-OMePh, 4- BuPh, 4-CNPh, 4-CF3OPh, 4-ClPh, t 4-CF3Ph, 4-FPh, 4-CF3SO2Ph, 3,5-CF3Ph, 4- BuCO2Ph, 51-94% yield at ambient temperature (Scheme 28A). Authors Manuscript pyridinyl, pyrimidinyl, 2-methylbenzo[d]thiazolyl, 6-chloropyridinyl projected a catalytic cycle which involves irradiation of 2+ B SET [Ru(bpy)3] (III) using blue light resulting in excited 2+ t N [Ru(bpy)3]* (II) which generated a powerful oxidant NiI 3+ 63 [Ru(bpy)3] (I). Afterwards, single electron oxidation of the OH Br N N 0 BP-H tetrahydroisoquinoline followed by hydrogen abstraction Ni D Ar' Ar O 2+ resulted in iminium ion A and recovering of [Ru(bpy)3] (III). N O Ar' Ar' On the other hand, interaction between NHC and aldehyde BP A Ar' H generated the nucleophilic Breslow intermediate B, which Accepted HAT hv O then captured iminium ion A to form a new intermediate C. ArBr O Ar' Ar Elimination of the NHC from intermediate C provided -amino Ar' BP* N Ar ketone D and allowed NHC E to re-enter in catalytic cycle again II Ni (Scheme 28B). Br O N Ar' N Ar NiIII B Br N

C Chemistry Scheme 27: (A) Ni-catalyzed photocatalytic dual benzoylation of aryl bromides; (B) proposed reaction mechanism. Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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A 2 NHC (5 mol%) O R O 2 Ru(bpy)3Cl2 (1 mol%) R 1 1 R R H m-DNB, CH2Cl2 N photons ~450 nm N Ar Ar

O 15 examples, 5-91% 1 R = Me, Et, n-Pr, CH2CH2SMe, ethylbenzene, N Br N 1-butenyl, cyclopropyl, CH2CH2CH2NPhth,

N Manuscript CH2CH2CH2OAc, i-Pr R2= H, 6,7-OMe

Br Ar= Ph, 4-MePh, 4-BrPh, 4-OMePh, 4-CF3Ph Br NHC

B

O R' N Ox N O N X 3+ N N Ru R1 R' N Ox H N N HO N * R1 2 B X R H

O I Accepted R' N NR + 2 N 2 N -H N N X NHC Catalysis R2 Photoredox Ru R' N R2 Catalysis O N N R' NR2 N NR 2 H X N X A O N R' E R' N II N N X N HO N + 1 2 N R' N O R Ru R2 2 X 2 R NR2 N R R1 N NR2 C N X NR2 F D Aza-Breslow III

Intermediate Chemistry Scheme 28: Photocatalyzed asymmetric sp3-acylation of tertiary amines and proposed catalytic cycle.

Suresh and co-workers developed a intermolecular tandem that bromo group as a better leaving group for this Cu-catalyzed O-arylation-oxidative acylation protocol transformation. Afterwards, the scope of various differently between 2,4-dihydro-3H-pyrazol-3-ones and O-halo aryl substituted 2-bromobenzaldehydes was explored and it was carboxaldehydes to synthesize chromone fused pyrazoles found that electron donating groups on 2- Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. using air as an ideal oxidant.64 The reactions were carried out bromobenzaldehyde were well accepted and provided the taking 0.5 mmol of 2,4-dihydro-3H-pyrazol-3-ones, 0.6 mmol resultant products in good yield. However, an electron- of o-halo aryl carboxaldehydes in the presence of CuI as withdrawing group such as fluorine gave the corresponding

catalyst, 1,10-phenanthroline as ligand, K2CO3 as base at 120 chromone fused pyrazole in moderate yield. Tetracyclic oC in DMSO as solvent. The reaction was used to prepare 25 chromone fused pyrazole was obtained in 66% yield with 1- chromone fused pyrazoles in moderate to good yields pre- bromo-2-naphthaldehdye on the other hand the reaction of Biomolecular

setting countable tolerance towards diverse substituents in N-Boc pyrazolone with 2-bromobenzaldehdye failed to deliver & substrate. During the initial screening of substrates 2- product. Moreover, this methodology was not found suitable bromobenzaldehdye provided better results than 2- in the case of heteroaromatic aldehyde like 2- chlorobenzaldehdye and 2-iodobenzaldehdye, suggesting chloronicotinaldehdye (Scheme 29A). Organic

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A 2 O 2 O R CuI (10 mol%) R 1,10-Phen (20 mol%) H C N O N N K2CO3 o N O 2 O 2 S X 3 DMSO, 120 C, 6 h R3 R R R1 R 1 R R3 R3 X= Br, Cl, I 27 examples, 25-74% Lawesson's N reagent N O O O Me Me Ph 1 N O Toluene, reflux, N O R = Ph, 3-NO2Ph, Me, benzyl 1 14 h 1 O O 2 R R Manuscript R = Me, Ph, n-Pr, t-Bu, CF3 93-96% N N N R3= H, 7-Me, 6-OMe, 6-F, 6-Br, 1 N O O N O N O O 8-Cl, 5-Cl, 7-F-6-OMe R = Ph, Me 2 Ph Ph Ph R = Ph, Me, Pr 51% 66% 51% R3= H, OMe

O B R2 O D Me O H O 3 Me N R3 R N X N O Pd/C, H2 1 N X R N O O Cu(I)X + Ln O N R3 (lll) O MeOH, rt, 16 h R3 LnCu 3 O 3 R2 R R 2 N R R1

N Accepted Reductive Oxidative X O elimination addition NH2 N LnCu(I)X Cu(III)Ln NO N 2 36-43% E X R1 A R3= H, 6-OMe, [1,3]dioxolyl O Base OH R3 Oxidative cross-coupling Ln(I)Cu O-Arylation O 2 N R R1 O X N R1 N R2 Reductive Base HX N Ln(II)Cu 3 elimination R 2 O R complexationN R3 X O C (Air) N 1 R1 R O Cu(III)Ln N O2 B X N R2 D Chemistry Scheme 29: (A) Cu-catalyzed ortho-arylation-oxidative acylation of 2,4-dihydro-3H-pyrazol-3-ones with ortho-halo aryl carboxaldehydes; (B) Plausible reaction mechanism; (C) Thionation of few chromone fused pyrazoles; (D) conversion of chromone fused pyrazoles into an A2-subtype selective adenosine receptor antagonist and its derivatives.

Based on the literature report and control experiments, a compounds were also treated with Lawesson’s reagent and plausible mechanism was proposed for this methodology the thione derivative was obtained in 93% yield (Scheme 29C). (Scheme 29B). The applicability of the developed method was The method had also been extended to synthesize an A2-

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. also checked for the gram scale and the targeted product was subtype selective adenosine receptor antagonist and its obtained in 68% yield. Moreover, some synthesized derivatives (Scheme 29D). Biomolecular & Organic

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B + 2- 2+ 2- + Ag S2O8 Ag SO4 SO4

path1A AgSO4 AgHSO4 O

OH O MeO B MeO SO + A 4 HSO4 OHC MeO path 1B CN Manuscript

H2O CN MeO CN MeO A O O ( ) n AgNO , Na S O 3 2 2 8 R1 + R2 ( ) 1 2 o n C R H R OH DMSO/H2O (1:1), 50 C O D O O O O HOH n = 1, 2 32 examples, 36-92% path 2A n= 1, 2 path 2B 1 water-assisted 1,2-HAT 1,2-HAT R = Ph, 4-CNPh, 4-CO2MePh, 4-OMe, 4-CHOPh, 4-MsPh, 4-AcPh, 2-CNPh, 4-(C(Et) OH)Ph MeO CN 2 MeO CN R2= Ph, 2-OMePh, 4-MePh, 4-OMePh, 4-OPhPh, -H2O 4-SMePh, 4-FPh, 4-ClPh, 4-BrPh, H, Bn, n-Bu, thiophenyl, benzpthiophenyl, benzofuranyl, F AgSO O OH cyclopropyl, cyclohexyl, cyclobutyl O E O 4 H AgSO4 Accepted AgHSO4 H2O path 3A, ET path 3B AgSO PCET 4

MeO CN

O O AgHSO4 AgSO4 O G OH CN PT MeO MeO CN

O H O H Scheme 30: (A) Ag-catalyzed ring opening acylation of cyclopropanols and cyclobutanols using aldehydes; (B) plausible reaction mechanism. Chemistry

Che et al. in 2018, described Ag-catalyzed ring opening outcomes and earlier reports, a probable mechanism was acylation of cyclopropanols and cyclobutanols through proposed as displayed in scheme 30B. intermolecular oxidative radical addition of aromatic 3.2.2. Acylation of sp2 carbons aldehydes using mild and neutral reaction conditions.65 1-(4- Methoxyphenyl)cyclobutan-1-ol and p-cynobenzaldehydye In 2013, Wang et al. developed an efficient and novel Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. were chosen as model reaction substrates to evaluate the approach for the synthesis of -unsaturated keto reaction parameters. Using the optimized reaction conditions, compounds by Cu-catalysed direct oxidative coupling reaction the substrate scope with respect to cyclopropanols, of alkenes and aldehydes with high atom economy.66 For the cyclobutanols and aromatic aldehydes was explored and 32 successful transformation of alkenes and aldehydes into the o  derivatives were prepared in 36-92% yield at 50 C (Scheme desirable -unsaturated keto compounds, the authors Biomolecular

30A). The reactions proceeded smoothly with the applied carried out the reactions using CuCl2 as most suitable catalyst

substrates bearing distinct functional groups of varying and TBHP as oxidant under nitrogen atmosphere. All the & electronic behaviour. To investigate the reaction mechanism, employed aldehydes and alkenes underwent coupling the reaction between model reaction substrates 1-(4- reaction effectively under the used reaction conditions methoxyphenyl)cyclobutan-1-ol and p-cyanobenzaldehdye irrespective of the positions and electron behaviour of was carried out using TEMPO under standard reaction substituents present either on the aromatic aldehydes or the conditions and a mixture of products was obtained without alkenes resulting in 18 derivatives in 30-80% yield (Scheme any acylated product. The results of control experiments ruled 31A). Authors investigated the possible mechanism by Organic out the formation of any possible acyl radical. Based on these performing the reaction in the presence of radical trapping

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substance 2,6-di-tert-butyl-4-methylphenol (BHT) under a free radical pathway as shown in scheme 31B. View Article Online standard reaction conditions, and the reaction found to follow DOI: 10.1039/D0OB01458C

B tBuOOH tBuO

O A 1 R2 O R2 R H O CuCl2, TBHP R3 R1 R3 R1 H N , 80 oC 2 O 18 examples, 30-80% [Cun] [Cun+1]~OH R1 2 R1= Ph, 3-MePh, 4-SMePh, 4-OMePh, 4-ClPh, A B R 4-MePh, 2-MePh, -naphthyl, thiophenyl 3 R2= H, Ph R R3= Ph, 2-MePh, 4-MePh, 4-t-BuPh, 4-FPh, 4-ClPh, 4-OMePh, 4-OAcPh 2 O R2 O R

1 3 1 3 R R Manuscript R R -H O 2 A

Scheme 31: (A) Cu-catalyzed direct oxidative coupling between alkenes and aldehydes; (B) plausible reaction mechanism.

In 2015, Li and co-workers developed a Fe-catalysed protocol oxygenated products in 22-65% yield after 1h of reaction at 50 for the acylation of terminal alkenes which undergoes oC (Scheme 32A). subsequent intramolecular oxygenation in a tandem manner Olefinic -diketones and olefinic -ketone esters smoothly to deliver functionalized 2,3-dihydrofurans having a reacted with benzaldehydes to provide theresultant quaternary carbon.67 The method bears a few salient features, dihydrofurans in moderate yields. However, the presence of a Accepted which include the insertion of carbonyl substituents and a SO2Ph group on the alkene suppressed the reaction with quaternary carbon containing various functional groups like benzaldehyde and the desired product was not observed. alkyl, aryl and esters. To check the applicability of the newly Moreover, the scope of aldehydes was also studied and both developed method several aldehydes (aromatic and aliphatic) aromatic as well as aliphatic aldehydes reacted effectively were treated with a variety of terminal alkenes in the under the optimized reaction conditions and afforded the presence of FeCl as catalyst, di-tert-butylperoxide (DTBP) as 2 products in moderate to good yields. However, in the case of oxidant and chlorobenzene as solvent under nitrogen cyclohexane carboxaldehdye and pivaldehyde, atmosphere. The authors prepared 17 different acylated- decarbonylation products were obtained. Chemistry Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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ARTICLE

4 3 A R R O 3 C O cat. FeCl2 1 R O CO2Me 2 R CO Me OMe R O 2 Ph + (tBuO) R1 H 2 Ph PhCl, 120 oC 2 O 4 O R OMe R HO 1 h, N MeO2C 2 MeO C HO B 2 A 17 examples, 22-65% CO Me OMe CO Me OMe R1= Ph, cyclopropyl, t-Bu, 4-MePh, 4-OMePh, 4-BrPh, thiopheyl O 2 O 2 Ph Ph R2= Ph, 4-MePh, 4-OMePh, 4-ClPh, naphthyl 3 OMe OMe R = COPh, (CO)-4-MePh, (CO)-4-OMePh, (CO)-4-ClPh, CO2Me, CO2Et, Me Manuscript R4= CO Me, CO Bn, Ph, Me MeO C HO MeO C O 2 2 2 C 2 D B O MeO C 2 O Ph O O Ph cat. FeCl2 R Ph + tt D Ph H BuO)2 Ph R4 R3 O TEMPO (2.0 equiv) MeOOC O 2 or BHT (2.0 equiv) R 1 not observed O R3 R R3 O O O OMe O O CO2Me Ph 1 1 2 2 O MeO2C O OMe OMe cat. FeCl R R R R 2 OMe R4 R4 O E + (tBuO) F Ph H 2 t MeO C O BuOH 2 (tBuO) OMe 2 [ O 55% F OH Accepted OMe e MeO CO Me O ] [Fe]n O OMe OMe * 2 O cat. FeCl * tBuO tBuO n 2 1 1 1 3 R H R 3 + R R R O + * t MeO * O O Ph H * ( BuO)2 1 MeO2C OH 2 R2 Ph R 4 O R4 O R tBuOH PTSA G

MeO CO2Me

MeO O

MeO2C 40% Ph

Scheme 32: (A) Fe-catalyzed tandem acylation of terminal alkenes; (B, C) comtrol experiments and (D) plausible reaction mechanism. Chemistry

To get an insight in the reaction mechanism, few control The idea of visible light mediated dual photoredox experiments were performed under standard conditions organocatalysis for the direct aldehyde Csp2 C-H (Scheme 32B). The use of radical scavengers TEMPO and BHT functionalization was also fruitfully utilized by Liu et al.68 The totally suppressed product formation and the alkene was protocol led to the generation of acyl radical species that recovered quantitatively supporting the addition of an acyl either underwent addition to electrophilic alkenes or Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. radical to the C=C bond in the initial step. The reaction of participated in the Ni-catalysed cross coupling reactions, benzaldehyde with the olefinic ketone resulted in the allowing the synthesis of a diverse range of unsymmetrical preferred dihydrofuran in 55% yield. An alkene having a ketones, present predominantly in various organic building hydroxyl group instead of a carbonyl group delivered a blocks. During the initial trials, benzaldehyde and 2- tetrahydronaphthalene as the major product, which on cyclohexeneone were chosen as the model substrates for the Biomolecular subsequent dehydration gave dihydronaphthalene. However, purpose of optimization and delightfully, moderate yields of

required the tetrahydrofuran product could not be obtained the desirable adduct could be formed. In order to investigate & via possible intermediates A and B. Based on these results, it the ability of quinuclidine as the HAT catalyst, a series of wasclear that the formation of the dihydrofuran was not experiments were performed using a number of co-catalysts. possible through the possible intermediate C or D (Scheme Also, a few photoredox catalysts were tested amongst which

32C). Based on the observations of experiments and literature [Ir[dF(3 )ppy]2(dtbbpy)]PF where (dF = 3,5-diFluoro; ppy = 2- reports, a tentative reaction mechanism was established phenylpyridine; dtbbpy = 4,4’-ditert-butyl-2,2’-bipyridine) (Scheme 32D). complex emerged to be a material of choice. Amongst the

various tested solvents, acetonitrile (MeCN) prove to be the Organic most favourable one resulting in high product yield. The

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control experiments significantly re-inforced the need of both purpose of photo irradiation. The authors View began Article theirOnline catalyst as well as visible light to mediate this transformation. investigation by questioning whether theDOI: photocatalyst 10.1039/D0OB01458C could Henceforth, the authors engaged themselves in the mission of provide the desired solution and in this endeavour they tested evaluating the scope of the reaction by subjecting a diversity a wide range of photoinitiators in the model reaction between of aldehydes and found the aliphatic linear as well as cyclohexaldehyde and diethyl maleate. Amongst all the tested branched chain aldehydes to be more reactive and affording photocatalytic sources, phenylglyoxalic led to higher product the desired products smoothly in moderate to good yields as yield with excellent selectivity. On further experimentation, it compared to the aromatic aldehydes (Scheme 33A). It was was found that the reaction could also take place in water and striking to note that in case of the weaker benzylic Csp3 C-H sunlight, but in the absence of either of these, the reaction bonds, selective Csp2 C-H activation could be achieved. failed to proceed. After optimizing the reaction conditions, Surprisingly, the branched aldehyde motifs yielded trace the authors examined the scope of substrates and found that amounts of decarbonylated product. while the branched aldehydes led to higher product yield and Manuscript selectivity, linear aliphatic aldehydes also rendered single The protocol was also applicable for an expansive range of product with good to excellent yield (Scheme 34A). olefin acceptor as evident from the obtained results. - Thereafter, alkenes and aliphatic esters were also screened. unsaturated ketones resulted in quantitative yields and Despite showing a wide generality, the protocol failed in case electron withdrawing substituents such as sulphones were of amides of maleic acid and other esters such as methyl well tolerated. However, in case of acrolein addition, the acrylate, methyl crotonate, and N-phenyl maleimide due to conversion was rather low. Also, wondrously, the polymerization issues. Also, when dibenzyl fumarate was cyclohexanecarboxyl radical was unable to open

subjected to the similar reaction conditions, the product was Accepted cyclopropane ring and starting material could be procured as obtained in lower yield. such as it remained totally unreactive. Furthermore, to add to the credentials, this strategy could also be extended to co- To probe the reaction mechanism, fluorescence quenching operative catalysis with Ni catalysed cross coupling between studies and UV-Visible experiments were performed. Through the generated acyl radical and organohalides (Scheme 33B). the results of the fluorescence test, it was interpreted that the acyl radical was not generated directly by the excited Ir(dFCF3ppy)2(dtbbpyPF6) O O quinclidine R3 phenylglyoxylic acid, unlike what had been observed in case 1 3 1 R R R H R2 MeCN, Ar, 34 W blue LED 2 of literature precedents. However, in case of esters of maleic 12 h R

20 examples, 31-99% acid (diethyl maleate and fumarate) quenching of Chemistry phenylglyoxylic acid was observed. On the basis of various mechanistic studies, a mechanism was proposed (Scheme R1 = Ph, 4-BrPh, ethylbenzene, cyclohexyl, cyclopentyl, n-hexyl, ethyl, i i Pr, Bu, CH2CH(CH3)Ph, CHEt2, etc. 34B). The irradiation led to the excitation of phenylglyoxalic 2 R = CO2Me, H, Me 3 t acid which formed an exciplex (inferred as a radical ion pair) R = CO2Me, H, CO2Et, CO2 Bu, COCH2Me, COMe, SO2Ph, CN with diethyl maleate via a photoinduced electron transfer

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Ir(dFCF ppy) (dtbbpyPF ) (PET) process. The exciplex was found to be in equilibrium Br 3 2 6 quinclidine O Br O . with another ion pair generated between PhCOCOOH and NiCl2 DME, dtbbpy R2 R1 R1 H 2 water. In absence of a HAT donor aldehyde, DMSO, Ar, 34 W blue LED R N2, 24 h photodecomposition occurred, quickly leading to the 8 examples, 15-60% formation of benzaldehyde. On the other hand, when the HAT

1 R = Ph, ethylbenzene, cyclohexyl, cyclopentyl, n-hexyl, ethyl, donor (aldehyde) was present, a HAT process with the Biomolecular CH2CH(CH3)Ph, CHEt2 R2 = 2-CN, 4-Ac aldehyde furnished the acyl and PhCOCOOH radical which slowly underwent decomposition to form benzaldehyde. The & Scheme 33: Ir catalyzed aldehyde Csp2 C-H functionalization of (A) alkenes and (B) arylhalides using aldehdyes. fluorescence quenching test also affirmed that the HAT process could not be initiated by the phenylglyoxalic acid on Kokotos and co-workers developed a green photo its own. This could also be the reason behind the difference in organocatalytic route for the C-H activation of aldehydes selectivity exhibited by other photointiators and which led to the selective hydroacylation of electron deprived phenylglyoxalic acid. The authors reached to the conclusion alkenes.69 For accomplishing this, phenylglyoxalic acid was that exciplex formation between phenylglyoxylic acid and utilized as the photocatalyst and household bulbs for the Organic dialkyl maleate is mandatory for this reaction.

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B O * O

H O A Ph COO 3 Ph H 2 O R PhCOCOOH O visible light 1 R H 1 2 3 R R R H2O, 4-20 h R3 R2 30 examples, 48-96% 2 O O * O R 1 i i n R3 Manuscript R = cyclohexyl, cyclopentyl, Pr, Bu, n-pentyl, Pr, CH(C2H5)2, hv CH(CH )CH CH , CH(CH )CH CH CH , ethylbenzene, Ph COOH Ph CO2H 3 2 3 3 2 2 3 Ph COOH PET R3 4-BrPh, 4-OMePh, etc. R2 = CO Et, CO Bu, CO CH(CH )CH CH , CO CH CF , 2 2 2 3 2 3 2 2 3 O CO2CH2CH2OPh, CO2CH2Ph, CO2CH2(4-ClPh), CO CH (4-MePh), CO CH (4-tBuPh), HAT 1 2 2 2 2 R2 R H R3 = CO Et, CO Bu, CO CH(CH )CH CH , CO CH CF , 2 2 2 3 2 3 2 2 3 O CO CH CH OPh, CO CH Ph, CO CH (4-ClPh), 2 2 2 2 2 2 2 O t O 3 OH CO2CH2(4-MePh), CO2CH2(4- BuPh), Ph, 4-ClPh, 4-OMePh R1 H R O R1 R2 R1 R2 Ph COOH R1 R3 R3

O Accepted

Ph H Scheme 34: (A) Photocatalytic hydroacylation of alkenes with aldehdyes; (B) proposed reaction mechanism.

Taking into account the fascinating advantages of (2,2,6,6-tetramethyl-1- piperidinyloxyl) -a radical scavenger photocatalysis, Yadav and team designed a promising metal that quenched the reaction completely. The formation of free, photocatalytic one-pot route to obtain chalcones via benzoyl-TEMPO adduct was confirmed by HRMS. radical denitrative benzoylation of β-nitrostyrenes.70 Visible To further gain an insight into the reaction mechanism, light was utilized as the energy source, N-hydroxyphthalimide electron paramagnetic resonance experiments were also (NHPI) as the reusable photocatalyst and acetonitrile was Chemistry carried out, which also confirmed the involvement of radical chosen as the green solvent. The primary reason for species in the reaction (Scheme 35B). Additionally, a kinetic employing NHPI as the catalyst was that it could readily isotope experiment was also conducted, which gave a KH/KD generate benzoyl radical photochemically from benzaldehyde ratio of 5.2, indicating the aldehydic C-H bond activation. and this in turn could cross couple with β-nitrostyrene to Apart from this, an on/off experiment was also carried out furnish chalcones. Sequentially, a number of control which signified the role of visible light in this process. Based Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. experiments were performed that delineated the significance on various mechanistic studies and previous literature of employing visible light and NHPI to afford the target reports, a plausible mechanism was proposed (Scheme 35C). chalcone compounds. After establishing the optimal As demonstrated, under visible light irradiation wherein 7 conditions for this visible light mediated synthesis, the Watt LED was used under inert N2 atmosphere, a radical was generality of the protocol was explored and it was found that formed by the migration of H atom of NDPI from O of the CO a broad range of β-nitrostyrenes and benzaldehydes Biomolecular group of imide. The hydrogen transfer from the aldehyde containing diverse electron donating as well as withdrawing moiety formed acyl radical along with the radical species B. & substituents could be applied that demonstrated impressive The acyl radical therefore underwent reaction with (E)-β- tolerance (Scheme 35A). It was further appealing to note that nitrostyrene to generate the benzylic radical, which a choleretic drug named “metochalcone” could also be eliminated the NO2 radical to form the targeted product. obtained using similar reaction conditions by the team of Thereafter, the NO2 radical abstracted H atom from B in order researchers. The protocol followed a radical mechanistic to regenerate NHPI that could further sustain the catalytic pathway which was confirmed via the addition of TEMPO cycle. Organic

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A O O NO white LED, 7 W 2 2 C R NHPI, MeCN, N R1 H 2 R1 R2 rt, 8-16 h O H 18 examples, 0-96%

R1 = Ph, 2-MePh, 2-OMePh, 4-FPh, 4-tBuPh, 4-CO2MePh, 4-MePh, 4-NH2Ph, 3-OHPh, 4-OMePh, 2,4-OMePh, thiophenyl, furanyl, O propyl O Manuscript R2 = Ph, 4-tBuPh, 4-OMePh, 4-NO2Ph, 2-NO2Ph, white LED 4-FPh, 2-NH2Ph, a-naphthyl, b-naphthyl, N O N OH 1-cyclohexenyl, A B Control experiment OH O O (I) TEMPO trapping experiment HNO2 O H O N OH white LED, 7 W NO2 B NO NHPI, MeCN, N OH 2 2 O rt, 8h O TEMPO not observed Accepted (II) Kinetic isotope effect experiment NO O H NO2 2 O

NO2 NO white LED, 7 W 2 O

NHPI, MeCN, N2 O D rt, 8h D O

D D D

D D D D Chemistry D D

Scheme 35: (A) photocatalytic one-pot benzoylation of -nitrostyrenes using aldehdyes; (B) control experiments; (C) plausible reaction mechanism.

Encouraged by this idea as well as the splendid results was investigated wherein a broad spectrum of aldehydes and encountered in case of sustainable photochemical olefins were subjected to the optimized conditions (Scheme

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. transformations, Jr. and co-workers set out in the task of 36A). Much to the delight of the researchers, the protocol performing epoxyacylation and hydroacylation of olefins showed great efficacy in furnishing the target compounds under visible light driven conditions employing methylene possessing either electron donating or withdrawing groups in

blue as the photoredox catalyst and persulphate (K2S2O8) as good to excellent yields. Aliphatic aldehydes and styrene the oxidizing agent.71 They utilized a single set of reagents for particularly reacted very well and yielded the target product

two diverse set of transformations. While performing the in good yield. Biomolecular optimization, the authors found that nearly 35% of the This strategy was also extended to benzaldehydes and non- & epoxyketone moiety could be obtained using 2.5 mol % of conjugated olefins and again both electron donating and methylene blue as photocatalyst, 1.0 mol K CO as the base 2 3 electron withdrawing substituents were well tolerated. and 2.0 equiv of K S O under 100 W irradiation. An increase 2 2 8 Unfortunately, aliphatic aldehydes failed to give good results. in product yield to 92% was observed on decreasing the Sytrenes also when subjected to the hydroacylation gave the amount of base employed for this protocol. A set of control corresponding epoxyketone in only traces. The results clearly experiments revealed the indispensable need of all the suggested that only non-conjugated long chain olefins can

reagents as well as light to render the desired moiety with Organic participate in this transformation (Scheme 36B). Again a good conversion percentage. The generality of the protocol plausible mechanism was proposed. A triplet state electron

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ARTICLE Organic & Biomolecular Chemistry

acceptor MB* was generated via the photoexcitation of generate radical A. This further provided anView access Article Online to methylene blue using a household lamp (100 W), which peroxide (B) by combining with hydroxyperoxylDOI: 10.1039/D0OB01458C radical that engaged in a single electron transfer (SET) with hydroperoxide was generated in the first step during SET. In the final step, anion produced from the persulphate alkaline hydrolysis that the targeted epoxyketone molecule was produced via the afforded the hydroperoxyl radical and methylene blue elimination of OH- from B under alkaline conditions. radical. Thereafter, through a hydrogen atom transfer (HAT) Methylene blue was regenerated via oxidation either aerially between benzaldehyde and hydroperoxyl radical, an acyl or in presence of persulphate (Scheme 36C). Similar radical was produced, which added to the styrene molecule to mechanism was also proposed for the acylation reaction.

A O R2 methylene blue O B 2 O K2S2O8, K2CO3 R methylene blue 1 K S O , K CO O R1 H R O 2 2 8 2 3 H O, 25 oC, 12 h Me Me 2 1 1 o R household bulb (100 W) R H n H2O, 25 C, 12 h n household bulb (100 W) 15 examples, 75-92% 9 Manuscript exa R1 = Ph, 2-ClPh, 3-ClPh, 4-ClPh, 4-MePh, 4-OMePh, n = 4, 5, 6 mple R1 = Ph, 4-ClPh,s,4-MePh, 4-OMePh 4-FPh, 2-CF3Ph, -naphthyl, cyclohexyl 2 67- R = Ph, 4-MePh, 4-OMePh, 4-ClPh 89%

C N

N S N

Household bulb MB 2- (100 W) S2O8 or O2

N N Accepted

N S N N S N MB MB* OOH O OOH O SET 1 I R OOH B R1 A OOH K2CO3 HAT III O II O 1 O R H O R1 R1 Chemistry

Scheme 36: (A) Epoxyacylation and (B) hydroacylation of olefins under visible light driven conditions usingmethylene blue as the photoredox catalyst; (C) proposed reaction mechanism.

Recently in 2019, Fe-catalyzed acyl-azidation of alkenes to delivering products in moderate to good yields. Styrenes synthesize unsymmetrical -azido ketones has been reported having alkyl substituents performed better than those by Ge et al. under mild reaction conditions. Aromatic and carrying halogens. Interestingly, vinylarenes containing an Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. aliphatic aldehydes were used as acyl radical precursors, ester or a free carboxylic group at the para-position also

azidotrimethylsilane (TMSN3) as azido source, and TBHP as an reacted effectively under the optimized reaction conditions oxidant in this transformation (Scheme 37A).72 The effects of providing moderate yields of the products. Moreover, various parameters including metal catalyst, solvent, additives heterocyclic compounds, -unsaturated carbonyl and temperature was studied taking styrene and compounds and conjugated dienes also resulted in the Biomolecular benzaldehyde as model substrates and TMSN3 as azido source corresponding azido ketones in moderate yields on treatment

to achieve the best reaction conditions. Interestingly, best with benzaldehyde and TMSN3. Subsequently, the scope of & product yield was obtained when styrene (0.5 mmol) was aromatic aldehydes, aliphatic aldehydes and -unsaturated treated with benzaldehyde (2.5 mmol) in the presence of Fe aldehydes was investigated. Aryl aldehydes having either

(OTf)3 (2 mol%) catalyst and TBHP (1.25 mmol) oxidant using electron-releasing or electron-withdrawing groups reacted

TMSN3 (1.25 mmol) after 24 h at room temperature. smoothly with moderate to good yields; however, electron- releasing groups were found to be more efficient than Having the optimized reaction conditions in hand, initially the electron-withdrawing groups.Few preliminary experiments authors investigated the scope of alkenes, o-, m- and p- were executed to investigate the reaction pathway and, Organic substituted styrenes (vinylarenes) with benzaldehyde depending on these studies, a plausible reaction mechanism

20 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

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for this acyl-azidation reaction was proposed as outlined in respective 3-acylspiro[4,5]trienone in 81% and 74%View yield.Article Online The DOI: 10.1039/D0OB01458C scheme 37B. arylaldehydes bearing a Br, OH, OMe, Me, CN or CO2Me group

A H Fe(OTf) (2 mol%) on the aryl ring were also found compatible with the optimal 3 N3 O TBHP (2.5 equiv) 2 1 R TMSN3 reaction conditions and the reactivity order was found to be R O MTBE, 25 oC, 24 h R2 R1 44 examples, 25-88% para>meta>ortho. Moreover, aliphatic aldehydes could be

R1= Ph, 4-OMePh, 4-t-BuPh, 4-ClPh, 4-OHPh, 2-Cl, easily reacted using the optimized reaction 3,4-MePh, 5-Cl-2-FPh, 3-F-6-MePh, -naphthyl, -naphthyl, furanyl, thiophenyl, benzofuranyl, conditions,resulting in thecorresponding spiro[4,5]trienones benzothiophenyl, 4-((trimethylsilyl)ethynyl)phenyl, 4-morpholinophenyl, cyclopropyl, propyl, cyclohex-3-en-1-yl, in good yields (Scheme 38A). 3-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl), etc. 2 R = Ph, 4-MePh, 4-t-BuPh, 4-FPh, 4-ClPh, 4-CO2MePh, 4-CO2HPh, 3-MePh, 3-ClPh, 2-MePh, 2-ClPh, ethyl, OMe, COOH, OC H , 4-methylthiazolyl, styrenyl, etc. 4 6 13 A R O R4 B Fe(lll)X2 O 1 N3 TBHP R

O Manuscript + 1 R2 O H R H n-BuOAc N O N O 110 oC, 36 h O 3 3 2 1 Fe(lll)X2 R R R O R R2 -92 TMSN3 28 examples, traces % R1= Ph, 4-OMePh, 3-OMePh, 2-OMePh, 2-OHPh, TMSOtBu 2-BrPh, 4-MePh, 4-CNPh, 4-CO2MePh, n-Pr,

N3 n-hexyl, undecanyl, 7-methoxy-3,7-dimethyloctanyl, O b 9-decenyl, 3,7-dimethyloct-6-enyl 1 2 R path a R = H, Bn, Me, 2-iodobenzyl 3 2 path O R = H, 6-Me, 7-Me, 6-I, 6-OMe, 9-OMe, 9-F R R2 c H O 4 path R = Ph, 2-OMePh, 4-OMePh, 4-MePh, 4-CNPh, Me + O R1 R1 pyridinyl A O TEMPO B t Accepted BuOOH tBuO + OH Fe(lll)X2(N3) TEMPO Ph Fe(lll)X2(OH)

N N 1 O R O Me CHO O O CO N O Ph t BuO Me

OMe TMSOH TMSN3 N O Me OMe tBuOH OMe B Scheme 37: Iron catalyzed acyl-azidation of alkene and plausible reaction mechanism. A Chemistry O 3.2.3. Acylation of sp carbons O Ph Ph OH

HO In 2014, Li and co-workers disclosed a metal-free protocol for OMe OMe N N O O the acylation of N-arylacrylamides with aldehdyes followed by Me Me D C an intramolecular cyclization to synthesize 3- t BuOH + H2O acylspiro[4,5]trienones.73 The flexibility of reaction was tBuOOH Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. demonstrated by the synthesis of 28 3-acylspiro[4,5]trienones O Ph in good to excellent yields. Reactions were performed HO between several electron-rich and electron-deficient N- OMe N O arylacrylamides and aldehydes (aromatic and aliphatic) using Me TBHP as optimum free-radical initiator oxidant without any Scheme 38: (A) Acylation of N-arylacrylamides with aldehdyes followed by an intramolecular cyclization; (B) plausible reaction Biomolecular catalyst under optimized reaction conditions giving the mechanism. respective products in 66-94% yield. Extensive screening of N- On the basis of control experiments and literature support, & arylacrylamides suggested that several groups including OMe, the authors designed a plausible reaction mechanism Me, CN on the aryl ring of the terminal alkyne were well (Scheme 38B). The mechanism involves the formation of tolerated, and electron-releasing groups showed better carbonyl radical A from the aldehyde through a single- reactivity in comparison to electron-withdrawing groups. N- electron transfer (SET) process in the presence of TBHP. arylacrylamides bearing substituents like o-Me/I, m-Me on Subsequent acylation of the alkyne with carbonyl radical A the aryl ring of nitrogen also performed well affording the resulted in vinyl radical B, which on selective ipso- good product yields. Moreover, the presence of a OMe or F Organic carbocyclization produced radical intermediate C. This group at the para-position of the N-aryl ring delivered the

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ARTICLE Organic & Biomolecular Chemistry

intermediate C, after selective addition of OH radical, afforded R3 View Article Online another intermediate D. Lastly, intermediate D on the DOI: 10.1039/D0OB01458CR3 2 O R O R2 oxidation in presence of TBHP, delivered the preferred 3- + TBAB(1 equiv), K2S2O8 (2 equiv) 1 H R1 R o acylspiro[4,5]trienone. DCE, 90 C, N2, sealed tube O O O O In 2015, Wu and co-workers also revealed a metal-free 35 examples, 37-86% R1= Ph, 4-MePh, 4-OMePh, 4-IPh, 4-ClPh, 4-ClPh,

tandem acylation of alkynoates with aldehydes followed by an 4-BrPh, 4-CF3Ph, 3-MePh, 3-OMePh, 3-ClPh, 2,4-ClPh, 2-MePh, 2-OHPh, n-propyl, i-Bu, cyclopropyl intramolecular cyclization resulting in 3-acyl-4-arylcoumarins. R2= 5,7-Me, 6-Me, 6-t-Bu, 6-OMe, 6-OPh, 6-F, 6-Cl,

6-Br, 6-CF3, 5-Me, 8-Me, 7-OMe The reaction proceeded under metal-free conditions in the R3= H presence of tetrabutylammonium bromide (TBAB) as additive Scheme 39: Metal-free tandem acylation of alkynoates with aldehydes followed by an intramolecular cyclization. and K2S2O8 as oxidant for the selective synthesis of biologically attractive 3-acylcoumarins.74 Under the optimized reaction To gain insight in the reaction mechanism for this newly

conditions, various differently substituted aldehydes and aryl developed protocol, the authors performed some control Manuscript alkynoates could be coupled in a metal-free experiments. The intramolecular and intermolecular kinetic acylation/cyclization process to obtain the 3-acylcoumarins in isotope, effects were measured using deuterium labeled

moderate to good yields. Aromatic aldehydes having electron- substrates in competing experiments and the kH/kD values releasing groups at the para-position of the aromatic rings were found to be 0.9 and 1.3, respectively. The observed low

coupled more efficiently than those containing electron- kH/kD suggested that the C-H bond cleavage is not the rate- withdrawing groups. Although, ortho- and meta-substituted limiting step in this transformation. Moreover, when the benzaldehydes were also appropriate for this conversion but reactions were carried out in the presence of the free radical a slight decrease in yields was found. Moreover, alkyl and scavengers TEMPO or BHT, no product formation was Accepted cyclic aldehydes also provided coumarin derivatives in observed and the adduct of p-tolualdehdye with TEMPO or moderate yields. BHT was observed, suggesting a free radical pathway of the reaction (Scheme 40A). In accordance with the observations Similarly, the aryl alkynoates with either electron-rich of the control experiments, a plausible mechanism following substituents or electron-poor substituents at the para- the free radical pathway was proposed (Scheme 40B). Initially position of the phenoxy ring reacted well and products were bis(tertrabutylammonium) peroxysulfate is generated by the obtained in good yields. However, in the presence of the reaction between peroxysulfate and TBAB, which get strong electron-withdrawing CF3-group on the phenoxy ring,

converted into the tetrabutylammonium sulfate radical anion Chemistry only 38% yield was obtained whereas, no product was formed at high temperature. This radical reacted with p- for the ortho-substituted system. Furthermore, aryl alkynoate methylbenzaldehyde to give an acyl radical A. Subsequently, with a methyl group at the meta-position of the phenoxy ring the selective addition of acyl radical A to the position of the resulted in a mixture of two regioisomers in a 1.6:1 ratio. C=O bond in alkynoate Y, resulted in the vinyl radical B. This However, the presence of a methoxy group at the meta- intermediate B then cyclized to the arene and formed another position delivered only one isomer in 76% yield (Scheme 39).

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. radical intermediate C. Next, a single-electron transfer from intermediate C to another sulfate radical could give cation D. This cation D upon deprotonation by the formed sulfate di- anion provided the 3-acylcoumarin derivative and another bisulfate anion. Biomolecular & Organic

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A D O O CHO O Ph O optimal conditions (a) Ph + 6 h, yield: 46% + KIE = 0.9 O O O O Ph D Manuscript D O O D Ph O D O O CHO O (b) D optimal conditions + Ph D D + 6 h, yield: 46% + KIE = 1.3 D O O Ph D Ph O O D

CHO Ph O O O optimal conditions (c) + TEMPO or BHT (2 equiv) O O Me Ph Me Accepted B O O O + heat (n-Bu N+-O) S O O S O (n-Bu N -) +- K2S2O8 + 2n-Bu4NBr 2KBr + 4 4 n-Bu4N O S O O O O

Ph O

n-Bu4NOSO3H - n-Bu4NOSO3 O O Me Ph O O

+ H O O Me

D Me Chemistry - O n-Bu4NOSO3 +- n-Bu4N O S O O

n-Bu4NOSO3H Ph O O

O O Me Me Ph C Ph O A Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM.

O O Me O O B Scheme 40: (A) Control experiments; (B) plausible reaction mechanism.

3.3. Acylation of heteroarenes/heteroaryls biochemistry and synthetic chemistry, and are widely Biomolecular distributed in natural products, biomolecules and other Heterocyclic compounds represent the largest and one of the

bioactive molecules. Heterocyclic scaffolds are major & most vital classes of organic compounds used in many constituents of biological molecules such as DNA, RNA, biological fields due to their importance for the treatment of vitamins, enzymes, chlorophyll, haemoglobin and many more. multiple illnesses and building blocks for industries. Presently, Therefore, pharmacists and organic chemists have been several heterocyclic compounds are known and due to the making extensive efforts for the formation and enormous synthetic research as well as their synthetic utility functionalization of heterocyclic molecules through the number of heterocyclic molecules is increasing rapidly developing versatile, atom- and step-economical efficient day-by-day. Heterocyclic compounds play a significant role in synthetic strategies. In this direction, Zhou and co-workers Organic almost all fields of science such as medicinal chemistry, (2012) explored the first Rh-catalysed regioselective oxidative

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C2-acylation of the ubiquitous indole (N,N-dimethyl-1H- Later in 2014, Yan et al. described a Pd-catalyzed ViewC-2 Articleacylation Online indole-1-carboxamide) by coupling with aryl/alkyl aldehydes of N-pyridinyl indoline with aliphatic andDOI: aromatic 10.1039/D0OB01458C aldehydes involving direct sp2 C-H bond cleavage and C-C bond by direct C-H functionalization.76 Various N-protected indoles formation strategy.75 The scope of N-protected indoles was were coupled with various aliphatic and aromatic aldehydes

explored with various aldehydes using Cp*Rh(MeCN)3(SbF6)2 in the presence of Pd(OAc)2 as catalyst, TBHP as oxidant and

as optimum catalyst and Ag2CO3 as oxidant. The presence of PivOH as additive. Benzaldehydes having electron- electron-releasing and electron-withdrawing groups at the withdrawing groups or electron-releasing groups at the para- aryl ring of the benzaldehyde did not affect the outcome of position provided the corresponding products in good yields. the reactions and good reactivity was demonstrated with N- However, relatively lower yield were observed in case of protected indoles irrespective of the position of the ortho-substituted benzaldehydes, because of steric

substituents. Benzaldehydes having Me, OMe, NO2, CF3, hindrance. -naphthaldehdyde and -naphthaldehdyde also COCH , CHO and COOMe, etc. at the para-position gave the

3 underwent the acylation reaction smoothly to afford the Manuscript corresponding products in 50-92% yields. Notably, 2- products in good yields. Interestingly, 5-methylfuran-2- furaldehyde, thiopene-2-carbaldehyde and 2- carbaldehyde and thiophene-2-carbaldehyde also naphthaldehdye underwent sp2-sp2 coupling efficiently and participated in this oxidative coupling to give the products in delivered the respective products in 73%, 85% and 90% yield, 64% and 74% yields, respectively. The reaction scope was not respectively. Interestingly, coupling between N,N-dimethyl- found to be limited to aryl aldehydes as several aliphatic as 1H-indole-1-carboxamide and paraformaldehdye resulted in well as conjugated aldehydes also effectively participated in the formation of dimeric 2,2'-biindolyl product with complete the reaction to give the products in good yields (Scheme 42A).

regiocontrol in 54% yield. Moreover, N-protected indoles Likewise aldehydes, several indoles containing functional Accepted having both electron-donating (OMe) and electron- groups such as methoxy, chloro, bromo, ester, etc. reacted

withdrawing (CF3, NO2, Br etc.) groups at the C6-position were smoothly to give products in moderate to good yields. readily converted into the targeted products in good to However, 3-substituted indole afforded a lower yield of the excellent yield (Scheme 41). acylated product due to steric crowding. The proposed

R1 mechanism for this protocol is depicted in scheme 42B. O R2 2 Cp*Rh(MeCN)2(SbF6)2 R N N O R1 H Ag CO , CH Cl , 85 oC O 2 3 2 2 O N N

28 examples, 45-93% Chemistry N 1 O R = Ph, 4-MePh, 4-OMePh, 4-NO2Ph, 4-CF3Ph, 4-COMePh, 4-CHOPh, 4-CO MePh, 4-ClPh, N 2 4-BrPh, 3-OMePh, 3-CF3Ph, 2-OMePh, 2-CF3Ph, benzo[d][1,3]dioxolyl, -naphthyl, thiophenyl, N N O N furanyl, n-Pr, cyclohexyl, 1 O O R = H, 6-NO2, 6-CF3, 6-OMe, 6-Br, 5-F, 4-F, 3-Me N N 54% (3 days) 45%

Scheme 41: Rh-catalyzed regioseletive oxidative C2-acylation of indole by coupling with aryl/alkyl aldehydes. Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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R1 B R1 A O 2 2 R Pd(OAc)2 (10 mol%) R N TBHP (2.0 equiv) N O N R1 H N O N N PivOH (2.0 equiv) N R= Ac, Piv toluene, 80 oC N Pd(OR)2

30 examples, 40-95% ROH Cyclopalladation R1= Ph, 4-OMePh, 4-MePh, 4-BrPh, 4-ClPh,

ROH Manuscript 4-CF Ph, 4-CNPh,3-ClPh, 3-MePh, Reductive 3 Elimination 2-OMePh, 2-FPh, 2-ClPh, 3,4-MePh, benzo[d][1,3]dioxol-5-yl,b-naphthyl, N 1 2 O N O -naphthyl, 5-methylfuran-2-yl, thiophenyl, O R Pd OR L N N O N cyclohexyl, n-hexyl, 2-methylprop-1-enyl, N 2,6-dimethylhepta-1,5-dienyl Pd OR N 2 N R = H, 6-CO2Me, 5-Br, 6-Cl, 5-OMe, L N 77% 3-Me, 3-CN, Oxidation 83% A

tBuO B O O 1 R1 R H tBuOH

Scheme 42: (A) Pd-catalyzed C-2 acylation of N-pyridinyl indoline with aliphatic and aromatic aldehydes; (B) plausible reaction Accepted mechanism.

A method describing the selective C-2 monoacylation and C- furaldehyde and thiophene-2-carbaldehyde provided the 2, C-7 diacylation through C-H bond functionalization of 1- corresponding C-2 acylated products in 79 %, 58 % and 54 % (pyrimidin-2-yl)-1H-indole using aldehydes was disclosed by yield, respectively. Indoles with electron-releasing and Govindasamy Sekar and his group in 2015.77 The authors electron-withdrawing groups at the C-5 position coupled synthesized fourteen C-2 monoacylated products, three C-2, effectively and yielded C2-acylated products in moderate C-7 symmetric diacylated products and two C-2, C-7 yields. Moreover, aliphatic and -unsaturated aldehydes, unsymmetric diacylated products in moderate to good yields when subjected to these reaction conditions, resulted in the Chemistry

using PdCl2 catalyst and TBHP (70 % aqueous solution in expected products in good yield (Scheme 43A). The use of 3 toluene) as oxidant in toluene. For monoacylation, 3 equiv of aldehyde and 5 equiv of TBHP under the same equivalents of TBHP were used, whereas, for diacylation, 5 reaction conditions provided the symmetric C2, C7-diacylated equivalents of TBHP were required. Aromatic aldehydes products through dual C-H bond functionalization with good containing both electron-releasing and electron-withdrawing yields (Scheme 43B). Whereas using two different aldehydes groups yielded 2-acylated products of 1-(pyrimidin-2-yl)-1H- (1.5 equiv. each) one after another resulted in the formation Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. indole in moderate to good yields. Sterically hindered of unsymmetrical diacylated products (Scheme 43C). naphthaldehyde and heteroaromatic aldehydes like 2- Biomolecular & Organic

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R1 A 2 O R R2 PdCl (10 mol%) N 2 N O R1 H TBHP N o N N toluene, 90 C, 24 h N

14 examples, 45-80% C 1 R = Ph, 4-MePh, 4-CNPh, 4-CO2MePh, 4-ClPh, 2-MePh, -naphthyl, furanyl, Ar' Manuscript PdCl2 (10 mol%) thiophenyl, pentyl, cyclohex-3-en-1-yl, TBHP N Ar'CHO Ar''CHO prop-1-enyl toluen N O 1 R = H, 5-OMe, 5-Br N e, 90 N N o Ar'' O N B R1 C, O 24 h PdCl2 (10 mol%) N TBHP N O R1 H N N o 1 N toluene, 90 C, 24 h R O N N O N O N Me O N N O N

NC Accepted 64% Me 68% N O N O N O N O N N N O N O N

Me 72% 52% 50%

Scheme 43: (A) Selective C-2 monoacylation of 1-(pyrimidin-2-yl)-1H-indole with aldehydes; (B) Symmetric and (C) Unsymmetric C-2, C-7 diacylation of 1-(pyrimidin-2-yl)-1H-indole with aldehydes.

Balachandran and co-workers in 2014 reported metal-free new carbon–carbon bond and produce the acylated

and solvent-free direct acylation of thiazoles through cross derivatives as a major products and homo-coupled side Chemistry dehydrogenative coupling (CDC) using TBHP as an oxidant.78 products as minor one in the terminating step (Scheme 44B).

In this method 16 acylated thiazole derivatives were O A 2 metal-free O R N synthesized with moderate to good yield by coupling various TBHP N 1 H R2 R R1 H neat, air aldehydes with thiazoles (Scheme 44A). The reaction 3 S S R 100 oC, 16 h conditions worked well with ortho-, meta- and para- R3 16 examples, 47-80%

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. substituted aldehyde derivatives. There appeared no R1 = Ph, 4-MePh, 4-FPh, 4-CPhl, 4-OMePh, 2,6-MePh, 2,6-OMePh, 2,6-ClPh, 3,4-OMePh 3-FPh, 4-OMePh, alteration in the product yield due to electronic and steric Me, thiophenyl 2 R = CH3 hindrance as all the 2-acylated thiazole derivatives were 3 R = H, CH3 obtained in good yield under optimized reaction conditions. B

OH + Aldehydes having electron-donating groups and halides as O O OH substituents resulted in acylated products in good yields Biomolecular

whereas, hetero-aromatic and aliphatic aldehydes provided N tBuOH N N N H & products in moderate yield. S S S S O 5% O O While analyzing the mechanistic pathway, it appeared that OH O the reaction proceeds with hydroxyl and alkoxyl radical H S H2O generation through hemolytic cleavage of TBHP. In the N 70% subsequent step, generated radicals abstract hydrogen from Scheme 44: (A) Metal and solvent-free direct acylation of thiazoles; sp2 C-H of 4,5-dimethylthiazole and the aldehydic C–H of (B) proposed mechanism. benzaldehyde, generating the corresponding free radicals. At Organic the closure, free radicals combines with each other to form a

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In 2017, Van der Eycken and his group established a mild and obtained in good yields (54-89%) when benzaldehydeView Article Online DOI: 10.1039/D0OB01458C versatile method for C2 C-H acylation of N-pyrimidylindoles contained electron withdrawing groups such as Br, CN, NO2

with aldehydes through dual photoredox/transition-metal and CF3. Interestingly, heterocyclic aromatic aldehydes, catalysis in batch and flow at room temperature.79 Initially the aliphatic acyclic and cyclic/heterocyclic aldehydes reacted authors explored various reaction parameters including efficiently to afford C2-acylated N-pyrimidylindoles in good to solvent, catalysts, photocatalysts and ligands to achieve excellent yields (Scheme 45A). Based on observations of optimal reaction conditions. Finally, the use of 10 mol% control experiments performed by authors and available

Pd(OAc)2 catalyst, 2 mol% of photocatalyst fac-[Ir(ppy)3], 20 literature reports, a plausible SET (single electron transfer) mol% Boc-Val-OH ligand and 4 equiv of 0.1 M TBHP in mechanism was designed as described in scheme 45B which acetonitrile delivered the best outcome after 20 h of blue LED initiates by the formation of a five membered palladacycle A

irradiation in a batch process. Whereas in a flow process only via interaction between N-pyrimidylindole and Pd(OAc)2 0.5 mol% of photocatalyst fac-[Ir(ppy) ] with slight excess of catalyst. In the meantime, the photocatalytic process

3 Manuscript oxidant (6 equiv. of 0.2 M TBHP in acetonitrile) along with the generated an acyl radical. The photo-excitation of the rest of the other reagents was found to be enough to give photocatalyst produced an excited state (Ir3+*) which get good product yields in just 2 h. With these optimized reaction oxidatively quenched by TBHP to generate a key radical conditions in hand, the scope of the reaction was determined intermediate t-BuO. This radical abstracts a proton from the by exploring various substituted benzaldehydes as coupling aldehyde to produce an acyl free radical, which on reaction partners of N-protected indoles. C2-Acylation of indole with intermediate A resulted in intermediate B. This derivatives with benzaldehyde bearing alkyl/aryl groups or a undergoes a single electron oxidation to PdIV, which closes the

methoxy group smoothly proceeded with good product photocatalytic cycle via a back-electron donation process. Accepted yields. However, hydroxylated benzaldehydes delivered Finally, reductive elimination resulted in the targeted product inferior yields. Furthermore, the acylated products were and regenerated the PdII catalyst. Chemistry Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. Biomolecular & Organic

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A PFA microreactor* R3 760 mM ID, 3 mL *Pd(OAc) (10 mol%) R3 R3 2 1 fac-[Ir(ppy)3] (2 mol%) R 1 Batch* R Boc-Val-OH (20 mol%) R2 TBHP (4.0 equiv) R2 N R1CHO ACN (0.1M) O N N O Blue LED, Ar atm. DG R2 2 h, rt DG DG room temp, 20 h 29 examples, 0-81% DG= pyrimidinyl, pyridinyl, Boc, methyl 18 examples, 0-95%

1 R1= 4- MePh, 4-OMePh, 4-OHPh, 4-FPh, 4-CF Ph, 4-CNPh, Manuscript R = Ph, 4- MePh, 4-PhPh, 4-OMePh, 4-OHPh, 4-FPh, 4-CF3Ph, 3 3-IPh, 3-NO Ph, -naphtyl, furanyl, furan-2-ylmethanol, 4-BrPh, 4-NO2Ph, 4-CNPh, 2,4,6-MePh, 3-OHPh, 3-BrPh, 3-IPh, 2  2,6-dimethylhept-2-enyl, 2,6-dimethylheptan-2-ol, cyclohexyl, 3-NO2Ph, -naphtyl, furanyl, thiophenyl, 2,6-dimethylhept-2-enyl, cyclohexyl tert-butyl piperidine-1-carboxylate, R2= H, 5-OMe, 5-F, 6-F, 7-Me tert-butyl pyrrolidine-1-carboxylate, 2 R3= H, Me R = H, 6-F R3= H B F

N

N N O N N N Pd(OAc)2

Reductive Accepted F Elimination AcOH C-H activation O

PdIV L PdII OAc N OAc N N N N N

C F A Oxidation H Ir3+ tBuOH O Acylation tBuO O PdIII Oxadative OAc O Quenching N F Chemistry Cycle F N 3+ N Ir Ir4+

t tBuOOH BuO B OH Scheme 45: Acylation of N-pyrimidylindoles with aldehdyes via dual photoredox/transition-metal catalysis in batch and flow and plausible reaction mechanism.

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. In early 2013, Antonchick and Matcha developed a metal-free reaction conditions. Moreover, aliphatic aldehydes could be cross-dehydrogenative coupling reaction between various reacted competently with isoquinoline using smaller amount 2 heterocyclic compounds and aldehydes for selective sp C-H of iodide and TMSN3. Aromatic aldehydes with electron- bond acylation (Scheme 46).80 The reaction proceeded releasing groups at the ortho, para and meta-position efficiently with all the applied heterocyclic compounds and delivered comparable yields. Whereas, the benzaldehydes

aldehydes giving a library of 62 compounds in the presence of with electron-withdrawing groups at the para-position gave Biomolecular

PhI(OCOCF3)2 as oxidant and TMsN3 as additive. Employing the better yields of the corresponding products in comparison of best reaction conditions, the scope of the isoquinoline their ortho- and meta-substituted derivatives. Moreover, & synthesis with various aldehydes was explored.. The reaction polymethoxy substituted benzaldehydes were also tolerated provided a broad substrate scope and aromatic aldehydes and provided products in good to excellent yield. Notably, having electron-releasing and electron-withdrawing groups at sulphur containing heterocyclic aldehydes provided cross- the aryl ring were selectively coupled to isoquinolines under coupled products in good yields without over-oxidation to metal-free conditions at ambient temperature. sulfoxides and sulfones (Scheme 46A). After exploring the

Polysubstituted benzaldehydes also provided the effect of aldehydes, the scope of various heterocyclic Organic desiredcoupling products efficiently under the developed molecules such as isoquinoline, quinoline, quinaxaline,

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acridine, benzothiazole and caffeine was also explored and all A by azide ions give PhI(N3)2.Intermediate B, View on Article thermal Online the heterocyclic compounds coupled smoothly under the homolytic cleavage, generates an azideDOI: radical 10.1039/D0OB01458C and a radical optimized reaction conditions to yield the targeted molecules intermediate C. Reaction between azide radical and aldehyde in good yields (Scheme 46B). generates nucleophilic acyl radical intermediate D. Subsequent attack of generated acyl radical onto protonated Through the observations of control experiments, a plausible heterocyclic E delivers intermediate F. Finally, re- mechanism has been proposed for this transformation aromatization of the intermediate F results the anticipated (Scheme 46C). The mechanism starts with a ligand exchange products. between PhI(OCOCF3) and TMSN3, which provides the intermediate B. A double exchange of trifluoracetyl groups in

PhI(OCOCF ) A C 3 2

Phl(OCOCF3)2 H CF3CO2H O Manuscript TMSN3, rt, 2 h N TMSN 3 HN N + 1 3 O R PhI(OCOCF3)2 H R O R1 A

N3 33 examples, 40-94% OCOCF3 O CF3CO2H Ph I R1= Me, heptanyl, ethylbenzene, cyclopropyl, cyclohexyl, i-Pr, CF CO TMS N R 2,6-dimethylheptan-6-olyl, 2-MePh, 2-FPh, 2-PhPh, 3-MePh, 3 2 B 3 D 4-MePh, 4-OMePh, 4-FPh, 4-IPh, 4-OBnPh, 4-OAcPh, 4-PhPh, OCOCF 3-FPh, 5-Cl-2-FPh, 2,4-MePh, 3,4-OMePh, 3,5-OMePh, 3 N Ph I 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,4,5-OMePh, 3,4,5-OMePh, C 4-OAc-2,6-OMePh, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, b-naphthyl, 2,4,6-OMePh, pentamethylphenyl, thiophen-3-yl, N dibenzo[b,d]thiophen-2-yl O

O H Accepted N HN CF3CO2 R H R E 2CF3CO2H CF CO PhI 3 2 F

B Phl(OCOCF3)2 O O H TMSN3, rt, 2 h 1 R R2 = + 1 N O R N Me OMe NO 2 R2 MeO MeO O Ph N

N N N N MeO MeO O Ph N N N Me R2 R2 R2 2 60% 66% 58% 90% R 35% Ac 84% Chemistry 2 R2 R Cl R2 CN N Br

N R2 2 N N Ph Cl N R2 N N R 81% 72% 77% 70% 65% 63%

Ac Ac Ac O N Cl N Me Br N N N N 2 Ac

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. R N 2 2 S N N R N R N Ac N Ac O N 75% 82% 67% 72% 74% 65% Ac 64% Scheme 46: Metal-free cross-dehydrogenative coupling reaction between isoquinoline, isoquinoline, quinoline, quinaxaline, acridine, benzothiazole and caffeine with aldehydes for the sp2 C-H bond acylation and plausible reaction mechanism.

A similar transition metal-free cross-dehydrogenative underwent a facile coupling with 4-(p-methoxyphenyl)- Biomolecular

coupling reaction for acylation of isoquinoline, quinoline and isoquinoline to afford the product in 41% yield. Moreover, & quinoxalines using aldehydes as acylating agents was quinoxaline, when coupled with 4-methoxybenzaldehdye and reported by Prabhu and his group in 2014.81 This method 4-methylbenzaldehdye delivered the acylated products were involved the use of a substoichiometric amount of in 66% and 44% yield (Scheme 47A). To explore the further tetrabutylammonium bromide (TBAB) as an additive and scope of the developed acylation method, quinoline was also

K2S2O8 as an oxidant. With optimized reaction conditions, subjected to this CDC strategy. Coupling of the quinoline with several isoquinolines were acylated using aromatic and 4-methylbenzaldehyde and butanal furnished the mixture of

aliphatic aldehydes to give the respective acylated products 2-acylated and 2,4-diacylated products in 1.2:1 ratio. On the Organic with 32-78% yields. Notably, thiophene-2-carbaldehyde also

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other hand, 4-benzyloxybenzaldehyde provided only 2,4- acyl radical B. Further, the acyl radical reactsView Article with Online the diacylated product in just 24% yield (Scheme 47B). heteroarene resulting in the formationDOI: of the 10.1039/D0OB01458C corresponding amidyl radical C. The formed amidyl radical gets deprotonated Based on the literature, the authors proposed a free radical with the sulfate anion and forms radical anion D. This radical mechanism (Scheme 48). The mechanism starts with the anion D transfers an electron to the persulfate resulting in the reaction between K2S2O8 and TBAB resulting in sulfate radical desired product. A, which abstracts hydrogen from the aldehyde to form the

A O TBAB (30 mol%) R2 K S O (2 equiv) N 2 2 2 8 1 + R R H N 100-110 oC, 2-12 h 1 DCE R O

30 examples, 32-78% Br N N R1= 4-OMePh, 4-OBnPh, 3,4-OMePh, O O 4-Me, 2,3,4-OMePh, 3,4,5-OMePh, Manuscript N N N 4-BrPh, 3-MePh, 3-OMePh, 2,3-OMePh, 2,3,4-OMePh, 3-OBnPh, O i-Bu, n-Pr, pentyl, hexyl, thionphenyl R2= H, 4-Ph, 4-OMePh, 5,6,7-OMe 77% 66% OMe 44% Me

Me B CHO O Me Me Me o BnO 8 h, 110 C N + CHO N O O 69% (1.2:1) O Accepted BnO BnO

N 12 h, 110 oC O N 24% O Me

2 h, 100 oC Me + Me CHO N Me N O 40% (1.2:1) O Scheme 47: Metal-free cross-dehydrogenative coupling reaction for the acylation of isoquinoline, quinoxaline and quinoline derivatives using aldehydes. Chemistry KBr O O properties.82 Moreover, benzofuran and benzothiopene +K-O S O O S O-K+ O O + - - + O O (Bu)4 NO S O O S O N (Bu)4 scaffolds containing an acyl group at the C-3 position are of O O + - 2(Bu)4N Br great interest for medicinal chemistry due to their KHSO4 antibacterial, anti-tumor, anti-arhythmic activities.83

O O O KBr Therefore, the development of new efficient protocols for the + - - + O (Bu)4 NO S O O S O N (Bu)4 - + O S O N (Bu)4 HO S O-N+(Bu) Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. O O 4 synthesis of 3-acylbenzofurans and 3-acylbenzothiophenes is O O A highly desirable. SET O O O In 2013, Zhao et al. published a pyridinyl group-assisted Pd- - + O S O N (Bu)4 N N O H R R catalyzed cross-dehydrogenative coupling reaction for the C- B O R O R 3 acylation of benzofuran and benzothiophene derivatives

D Biomolecular KHS2O8 using TBHP as an oxidant under air.84 Several derivatives of O K2S2O8 aldehyde were coupled with benzofuran and benzothiophene & R N N in the presence of Pd(OAc)2 as catalyst, TBHP as oxidant in chlorobenzene at 120 oC. The reaction exhibited a broad O R C Scheme 48: Plausible reaction mechanism for metal-free cross-dehydrogenative scope and high compatibility with the functional groups such coupling reaction of the acylation of isoquinoline, quinoline and quinoxaline derivatives. as OMe, Me, NO2, CN and halogens, etc. and provided Benzofurans and benzothiophenes are highly privileged excellent yields (89-97%) of the desired products regardless structural moieties, which are present in several natural the position of the substituents on the benzene ring of Organic products and exhibit a broad spectrum of biological benzaldehydes. However, dimethoxy-substituted benzaldehyde provided a slightly lower yield of acylated

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products of benzofuran and benzothiophene. Moreover, gain mechanistic insight. The kinetic isotope effectView Article (kH/k OnlineD = heterocyclic aldehydes such as thiopehen-2-carbaldehyde 2.79) revealed that C-H cleavage might beDOI: involved 10.1039/D0OB01458C in the rate and 2-furaldehyde also reacted smoothly and the limiting step. corresponding products were obtained in good to excellent R2 R3 R3 yields. Unfortunately, no product was formed in case of O 2 Pd(TFA)2, TBHP R aliphatic aldehyde (Scheme 49A). As per previous reports, the N + N H R1 DCE, 80 oC, 16 h tBu tBu authors designed a plausible mechanism to rationalize this O R1 O O methodology as presented in scheme 49B. Cl 10 examples, 40-78%

1 A R O R1= Ph N O R2= H, 4-Me, 5-OMe, 5-Cl, 5-F Pd(OAc) (5 mol%), TBHP N + 2 t 3 1 R Bu R = H, 2-Me, 3-Me, 3-Me-3-Ph, X N H R PhCl, 120 oC, 20 h t O O X Bu 3,3-Me-2-Ph N Ph O O X= O & S

50% Manuscript 22 examples, 79-97% 69% R1= Ph, 4-MePh, 4-OMePh, 4-FPh,

4-NO2Ph, 4-CNPh, 3-OMePh, Me 3,4-OMePh, 2-ClPh, furanyl, Me thiophenyl O Pd(TFA)2, TBHP N + 1 o B N H R DCE, 80 C, 16 h tBu N tBu R1 O O X Pd O O O N HX X 13 examples, 28-81% tBuO 1 + 1 R H R 1 R = Ph, 4-OMePh, 4-CF3Ph, 3-OMePh, 3-NO2Ph, X 2-ClPh, 2-F-4-OMePh, benzo[d][1,3]dioxolyl, A 5-methylfuran-2-yl, cyclohexyl, i-Pr, pentyl, 2-methylprop-1-enyl Accepted

PdX2 Scheme 50: Pd-catalyzed oxidative C-7 acylation of indolines and O R1 carbazoles with aldehydes. X X R1 L O N Later, in 2014 Cheng et al. reported a regiospecific Minisci X acylation of phenanthridine based on a cross- X N B Scheme 49: Pd-catalyzed cross-dehydrogenative coupling reaction for the C-3 dehydrogenative coupling strategy via thermolysis or acylation of benzofuran and benzothiophene derivatives and plausible reaction 86 o mechanism. photolysis. Under thermal conditions (100 C) the acylation of phenanthridine with aldehydes was carried out using a Kim and co-workers in 2014 disclosed a Pd-catalyzed oxidative substoichiometric amount of the phase transfer catalyst coupling reaction for the selective C-7 acylation of substituted Chemistry tetrabutylammonium bromide (TBAB, 30 mol%) and K2S2O8 as 85 indolines using aldehydes via a C-H activation approach. The oxidant. Interestingly, a preliminary research based on reactions were carried out between various N-pivaloyl literature reports indicated that phenanthridine could be indolines/N-pivaloyl carbazoles and aromatic/aliphatic acylated selectively at room temperature replacing the aldehydes using Pd(TFA)2 as catalyst, TBHP as oxidant in DCE TBAB/K2S2O8 system with (NH4)2S2O8 and using 5 mol% of fac- as solvent at 80 oC to prepare 24 derivatives. The coupling Ir(ppy)3 as photocatalyst under visible light irradiation. Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. reaction of C-2 or C-3 unsubstituted indolines with However, the reaction proceeded slowly (48 h) under benzaldehyde afforded the corresponding acylated products photocatalytic reaction conditions in comparison to thermal in moderate yields. C-2 and C-3 alkyl/aryl substituted reaction conditions (12 h). Several aromatic aldehydes with indolines also underwent the oxidative acylation reaction to electron-releasing (Me, OMe) and electron-withdrawing (F, Cl, provide products in moderate to good yields under the

Br, OAc etc.) groups at the aromatic ring were coupled with Biomolecular developed reaction conditions. Electron-rich as well as phenanthridine under the optimized thermal conditions as

electron-deficient benzaldehydes were found to favor the well as photo-catalytic conditions and targeted products & acylation reaction irrespective the position of the substituents could be obtained in moderate to good yields. Benzaldehydes on the phenyl ring and afforded the products in good to high with di- and tri-methoxy substituents triggered good results in yields. Isobutyraldehyde, cyclohexanecarbaldehyde and 1- both conditions. Interestingly, 4-fluorobenzaldehyde hexanal provided moderate yields. However, 5-methylfuran- provided the maximum yield of 80% under thermal 2-carbaldehyde and 3-methylbut-2-enal delivered the conditions. Unfortunately, no product was obtained with 4- products in poor yields (Scheme 50). Two parallel reactions of nitrobenzaldehdye and 4-N,N-dimethylbenzaldehydes in N-protected carbazole derivatives and their deuterated Organic analogues with benzaldehyde were performed in order to

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either of the conditions. Aliphatic aldehydes provided inferior were achieved in moderate to good yields after 12View h. ArticleAromatic Online DOI: 10.1039/D0OB01458C product yields (Scheme 51A). aldehydes with electron-releasing (CH3, OCH3, OCH2O) and mild electron-withdrawing (F, Cl, Br) groups on the benzene Based on the literature and experiments, a possible ring smoothly favored the selective C3-acylation of coumarin photocatalytic pathway was proposed (Scheme 51B). The in moderate to good yields. However, aromatic aldehydes persulfate anion can be reduced by visible light excited 3+* with electron-withdrawing groups afforded inferior product [Ir(ppy)3] to give sulfate and the sulfate radical anion A 4+ yields in comparison to aldehydes bearing electron-releasing along with [Ir(ppy)3] . H-Atom abstraction from the aldehyde groups at the aryl ring. The steric hindrance on aromatic by radical A gives acyl radical B which on addition to aldehydes did not affect this transformation since ortho- phenanthridine afforded amidyl radical C. Deprotonation of substituted aldehydes and -naphthaldehyde smoothly the -proton in the amidyl radical C by the sulfate anion 4+ generate the corresponding products in moderate yields. generates radical anion D. Reductive quenching of [Ir(ppy)3]

3+ Unfortunately, aliphatic aldehydes failed to deliver the Manuscript by radical anion D through SET generates [Ir(ppy)3] targeted products. Furthermore, coumarin substituted with sustaining the photocatalytic chain. electron-rich (OCH3, OCH2CH3, etc.) and electron-poor (OH,

OCOCH3, NO2, etc.) groups at the C6 or C7-position were A found to give the corresponding products in moderate yields K2S2O8, TBAB, DCE O 110 oC, 3-12 h (Scheme 52A). A series of N-methyl quinolinone derivatives + or R1 H O N (NH4)2S2O8, fac-Ir(ppy)3, DMSO, N was also examined successfully using the optimized reaction rt, visible light, 48 h R1 conditions and acyl groups were exclusively attached to the 19 examples, 0-81% (0-73%)*

C3-position of 2-quinolinones delivering 55-77% yield of the Accepted R1= Ph, 4-ClPh, 4-BrPh, 4-FPh, 4-MePh, 4-OMePh, 4-NO2Ph, 2-ClPh, 2-BrPh, products. On the bases of control experiments and previous 2-MePh, 2-OMePh 2-OAcPh, naphthyl, -naphthyl, 3,4-OMePh, 3,4,5-OMePh, reports, a plausible reaction mechanism was proposed by 4-N(Me)2Ph, n-Bu, hexyl authors as depicted in scheme 52B. *photocatalysis yield is given in parenthesis

B HSO SO 2- A R2 4 4 R2 O R3 FeCl (10 mol%) O 2 TBHP (4 equiv) R1 R3 + 1 o O O R H PhCl, 120 C, N2 N N X O O O SET 1 X= O & NMe R1 D R 25 examples, 38-72% O N R1= Ph, 4-MePh, 4-OMePh, 4-FPh, 4-ClPh, Chemistry C R1 2-OMePh, 2-ClPh, 2-BrPh, 3,4-OMePh, 2,4-ClPh, -naphtyl, benzo[d][1,3]dioxolyl, O 5-methylthiophene-2-yl, 5-methylfuran-2-yl + + R2= H, Me. Ir(ppy)3 Ir(ppy)4 R1 H 3 R = H, 7-OMe, 7-OH, 6-NO2, 7-OAc, 7-OC2H5, 6-Br O SO4 Fe(ll)X2 B t + A 1 t BuO OH (or Fe(lll)X2OH) Ir(ppy)3 * R Initation: BuOOH + B or heat 2- S2O8 SO 2- Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. 4 O HSO4 O tBuO O X O R1 R1 H R1 N X O t Scheme 51: (A) Acylation of phenanthridine with aldehydes via BuOH A thermolysis or photolysis; (B) proposed reaction mechanism. Fe(lll)

87 Fe(ll) In a span of four years (2015-2018), four individual studies Biomolecular on the application of aldehydes as acylating agents were O O

published for the selective direct C3-acylation of coumarins. R1 R1 & In 2015, Fe-catalyzed cross-coupling of coumarins was carried X O X O H+ B out with aromatic aldehydes in the presence of TBHP oxidant Scheme 52: (A) Fe(II)-catalyzed cross-coupling of coumarins for the 87a under N2-atmosphere by the team of Ling-Bo Qu. Initially, selective direct C3-acylation; (B) plausible reaction mechanism. several aromatic aldehydes (1.0 mmol) were coupled with Later in 2016, Aihua Zhou and co-workers developed a new coumarin (0.25 mmol) under the optimized reaction coupling reaction for the selective C3-acylation of coumarins conditions using FeCl2 as catalyst, TBHP as oxidant in toluene by a sp2 C-H functionalization process involving aldehydes in Organic at 120 oC under nitrogen atmosphere. The targeted molecules the presence of a Cu-catalyst and TBHP as oxidant (Scheme

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87b 53A). Various coumarin derivatives were acylated OMe) groups or mild electron-withdrawing groupsView Article (F, Online Cl) regioselectively at the C3 position by aldehydes and all reacted proficiently and delivered the productsDOI: 10.1039/D0OB01458C in high yields. substrates reacted proficiently to produce the respective The scope of substituted coumarins was also explored using products in moderate to good yields in the presence of CuO as 6-methyl-coumarin and 6-chlorocoumarin and the expected catalyst and TBHP as oxidant at 90 oC after 24 h. Aromatic products could be obtained in good yields. Moreover, aldehydes with electron-releasing groups (OMe, Me, tBu, etc.) treatment of acetaldehyde with coumarin afforded 88% of the and the electron-withdrawing bromine group were found desired product. The control experiments revealed that the suitable for this transformation. Nevertheless, in case of reaction followed a free-radical mechanism since the addition nitrobenzaldehyde no expected product could be observed, of free radical scavenger TEMPO to the reaction mixture whereas iso-butyraldehdye delivered the C3-acylated product inhibits the formation of the product completely. The in 48% yield. Noticeably, 2-furaldehyde also afforded the proposed mechanism is depicted in scheme 54B. This starts product upon coupling with coumarin, and 6-methyl coumarin with the reaction between Aliquat-336 Manuscript

in 65% and 63% yield, respectively. Moreover, the presence of (tricaprylmethylammonium chloride) A and K2S2O8 resulting in substituents on the coumarin did not alter the reaction the formation of tricaprylmethylammonium persulfate B, outcome and good yields were obtained. The proposed which generates tricaprylmethylammonium sulfate radical C mechanism for this protocol is presented in scheme 53B. on heating. Then, acyl radical E is generatedvia the reaction

A R1 between benzaldehyde and the sulfate radical B and this O process is accompanied by the removal of 2 O R CuO, TBHP 2 1 + R R H o O O 90 C O O tricaprylmethylammonium hydrogensulfate D. Radical Br 15 examples, traces-68% addition of E to the 3-position of coumarin forms resonance Accepted

R1= Ph, 4-OMePh, 4-MePh, 4-t-BuPh, stabilized benzyl radical F. Finally, removal of a hydrogen atom 4-BrPh, 2-OMePh, 2-NO2Ph, from F by another sulfate radical C afforded the desired furanyl, t-Bu O R2= H, 6-MePh, 6-OMePh, 6-t-Bu, product together with D. Tricaprylmethylammonium chloride O O gets regenerated by the reaction between 52% tricaprylmethylammonium hydrogensulfate D and KCl. B O 1 O R R1 H A t t O 2 2 BuOOH BuO + OH R K2S2O8 (1.2 equiv) R R1 Aliquat 336 (30 mol%) O H R1 + O O PhCl, 100 oC, 8 h O O Chemistry 13 examples, 70-90% O O R1= Ph, 4-MePh, 4-OMePh, 4-FPh, Cu(l) Cu(lI) 4-ClPh, 2-OMePh, 2-ClPh, Me R2= H, Me, Cl 1 R1 O R R1 B 2KHSO4 2KCl O O O O + O O O O O O 2R3MeNCl O 2R MeNOSO H O B A A 3 3 H Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. 2K2S2O8 D R R Scheme 53: (A) Cu-catalyzed C3-acylation of coumarin; (B) plausible E reaction mechanism. O O O 2KCl F R MeNOSO (R MeN) S O 3 3 3 2 2 8 R H C Subsequently in 2016, Peiman Mirzaei and his team worked B 2R3MeNOSO3 O C on a transition metal-free cross-dehydrogenative coupling Heating R R= Octyl R3MeNOSO3H D

reaction for the synthesis of 3-acylcoumarins. Reactions were O O Biomolecular carried out by heating a mixture of coumarins and aldehydes Scheme 54: (A) Metal-free cross-dehydrogenative coupling for C3-acylation of

coumarin; (B) proposed reaction mechanism. & in the presence of K2S2O8/Aliquat-336 system in chlorobenzene. Various substituted coumarin and aldehyde Recently, our group has developed a highly proficient, metal- o derivatives were coupled at 100 C for 8 h to synthesize 14 free approach for the regioselective C3-acylation of coumarins derivatives of 3-acylcoumarins in good to excellent yields with aromatic aldehydes using tert-butyl peroxybenoate 87c (Scheme 54A). The electronic behaviour of the substituents (TBPB) as free radical initiator (Scheme 55).87d Various present on the benzene ring of the aromatic aldehydes played differently substituted aromatic aldehydes having electron- a key role for the yields irrespective of their positions.

releasing and electron-donating groups were reacted with 7- Organic Aromatic aldehydes having either electron-releasing (Me, methoxy coumarin under the optimized reaction conditions.

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All applied aromatic aldehydes delivered the anticipated intermediate A via co-ordination of the palladiumView with Article the Online O- products in moderate to good yields at 90 oC after 24 h. Also, atom of quinoline-N-oxide and subsequentDOI: 10.1039/D0OB01458C electrophilic other derivatives of coumarin produced the desired products attack at the C8-position. Subsequently, complex A gets in good yields upon treatment with benzaldehyde. converted into another intermediate B through nucleophilic

Unfortunately, neither aromatic aldehyde nor coumarin addition of H2O at the C2-position of the quinoline. In the

having strong electron-withdrawing NO2-group furnished the meantime, an acyl radical was generated from the aldehyde corresponding acylated compound. Moreover, iso- in the presence of TBHP. The reaction between intermediate butyraldehyde and pyridine-2-carbaldehyde also resulted in B and the acyl radical afforded the oxidative addition the acylation of coumarin at C3-position in 41% and 60% yield, intermediate C as a Pd(III) or Pd(IV) complex. Finally, respectively. Furthermore, N-methylquinolone also delivered intermediate C gave the desired product through reductive the individual C3-acylated product upon treatment with elimination and regenerated Pd(II). simple benzaldehyde under the optimized reaction Manuscript conditions. CHO

2 PdCl (10 mol%) X O R 2 2 X O + TBHP (4.5 equiv) R O TBPB 1 2 2 R N R R 1 O N 1 + R DCE/H2O (15:1) H H R benzene, 24h O 140 oC 90 oC O O 1 X= O & NMe R 15 examples, 0-75%

1 R = Ph, 4-MePh, 4-BrPh, 4-NO2Ph, 2-BrPh, 26 examples, 30-95% 2-FPh, i-Bu, pyridenyl O N 1 2 R = H, 4-Me, 4-OMe, 4-F, 4-Cl, 4-Br R = H, 7-OMe, 7-Br, 7-OAc, 6-NO2 H 2-Me, 2-OMe, 2-F, 2-Cl, 2-Br, 3-Me, O 3-OMe, 3-F, 3-Cl, 3-Br, 3-CF3, 3,4-Me, Scheme 55: Regioselective C3-acylation of coumarin with aldehydes. Accepted 2,4-Cl 30% R2= H, 3-Me, 3-Br, 5-OMe, 6-Me, 6-F, 6-Cl In 2016 Wu and his team described a one-pot process for the selective formation of 8-acylated-2-quinolinones starting

O N N from quinilone-N-oxides and aldehydes using a Pd-catalyst PdCl H 2 O and TBHP as oxidant via the formation of N-oxide-chelated COPh HCl palladacycle.88 A total of 26 8-acylated-2-quinolinones were H2O synthesized in good to excellent yields starting from various HO N N quinoline-N-oxides and benzaldehydes in the presence of H O Pd Cl O Pd COPh

H Chemistry PdCl2 catalyst, TBHP (5-6 M in decane) as oxidant, water as Cl A 2 additive and DCE as solvent at 140 oC for 24 h. (Scheme 56A). C H O HO 2 t Benzaldehydes having electron-releasing (Me and OMe) and BuO N H O O H weak electron-withdrawing (F, Cl and Br) groups at the para- O Pd Cl R R H position of the aryl ring gave the corresponding products in B 2 tBuOH good to excellent yields. However, proficiency of acylation Scheme 56: (A) Pd-catalyzed selective C-8 acylation of quinilone-N-oxides using aldehydes; (B) plausible reaction mechanism. Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. was slightly affected by steric hindrance as p- methylbenzaldehyde gave a higher yield than o- and m- Manna et al. in 2017 developed visible light photoredox and methylbenzaldehyde and a similar pattern was observed for palladium (II) catalyzed regioselective direct C-2 acylation of methoxy and halogen-substituted benzadehydes. 3- N-pyrimidine protected indoles using aldehydes as acylating (trifluoromethyl)benzaldehyde provided the acylated product agents and TBHP as acyl radical generator.89 Various in just 43% yield. Furthermore, disubstituted aromatic differently substituted aromatic, heterocyclic and aliphatic Biomolecular aldehydes also provided good yields of the desired products. aldehydes were coupled with N-pyrimidine protected indoles & Substituted quinoline-N-oxides were also coupled smoothly to synthesize a library of 27 acylated indole derivatives in good with benzaldehyde and the positions of the substituents did to excellent yield (Scheme 57A). Aromatic aldehydes having not interfere with reaction outcomes significantly improving electron-releasing (Me, OMe) groups resulted higher yield the synthetic effectiveness of this protocol. than those of containing electron-withdrawing (Br, CN) Based on several control experiments such as free radical groups. -Naphthaldehyde and thiophene-3- trapping and kinetic isotope effect, a plausible mechanism carboxyaldehdye resulted the 75% and 74% yield of was proposed by the authors as presented in scheme 56B. The corresponding products. Aliphatic aldehydes such as Organic mechanism starts with the formation of a palladacycle dimer cyclohexanecarbaldehdye, pentanal and 3-methylbut-2-enal

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2+ 2+* delivered good product yields. Similarly the scope of 57B). Initally, Ru get excited to Ru in presenceView Article of light,Online substituted N-pyrimidine protected indoles was established which transfer a single electron to TBHP DOI:(t-BuOOH) 10.1039/D0OB01458C to produce and high product yields were achieved irrespective of nature OH- and t-BuO. via the cleavage of O-O bond and oxidized to and position of substituent. Interestingly, protected Ru3+. Then t-BuO. abstracts hydrogen from aldehyde to tryptophan and carbazole also delivered the desired mono generate acyl radical. On the other side, N-pyrimidyl indole acylated products in moderate to good yields. undergoes cyclopalladation to form intermediate A. To get insight into reaction mechanism authors performed Subsequent oxidative addition of intermediate A to acyl few control experiments. When standard reaction was carried radical delivered cyclopalladated Pd(III) intermediate B, which out in presence of 2 equiv of TEMPO the reaction quenched may be oxidized to Pd(IV) species C through a single electron completely and no desired product could be obtained. transfer to Ru3+ resulting in reduction of Ru3+ to Ru2+. Species Moreover, in the absence of photoredox catalyst very poor C finally delivered the corresponding acylated product and yield was achieved and no reaction was observed in absence Pd(II) species by reductive elimination process. Manuscript of TBHP. With the help of these experiments and literature

reports a mechanism was given for this reaction (Scheme

3 A R R3 Pd(OAc)2 (10 mol%) O 1 TBHP (3 equiv) R B 2 Me R Ru(bpy)3Cl2.6H2O (2.5 mol%) R2 R1 H N N O N MeCN (0.1 M) N N N blue LED, rt, 16-48 h II N N Pd (OAc)2 N O

27 examples, 40-92% PdIV OAc 1 N L

R = Ph, 4-MePh, 4-OMePh, 4-BrPh, 4-CNPh, 4-OAcPh, 4-CF3Ph, Accepted 3-OPhPh, 3,4-ClPh, 3,4-OMePh, 3,5-OMePh, 3-benzothiophenyl, N 3-thiophenyl, -naphthyl, cyclohecyl, n-pentyl, 2-methylprop-1-enyl C N Me II 2 Pd OAc R = H, 5-Br, 5-OMe, 5-F, 4-CN, 5-Me, 5-Cl N R3 = H, Me N CO2Et Me CO2Et N Ru2+ PhthN PhthN S O A Blue PdII OAc N LED Ru3+ N N N N O O O O N N Me Ru2+ N N N N t N t BuO 68% BuOOH B 50% Me 72% OH O TBHP Chemistry

H

Me Scheme 57: (A) visible light photoredox and palladium (II) catalyzed regioselective direct C-2 acylation of N-pyrimidine protected indoles using aldehydes; (B) plausible reaction mechanism.

In 2017 Maiti et al. developed highly regioselective Pd- N-pyridyl carbazole resulted in monoacylated products on

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. catalyzed direct ortho-mono and diacylation of carbazole at coupling with aromatic aldehydes under optimized reaction C1 and C8 positions using aldehydes as acylating agents via C- conditions (Scheme 58B). Authors have given a free-radical H bond activation.90 Authors prepared 20 diacylatd and 4 promoted plausible reaction mechanism for the diacylation of mono acylated derivatives in 27-94% yields by coupling N-pyridyl carbazoles (Scheme 58C). various aromatic and aliphatic aldehydes with N-pyridyl

carbazoles (Scheme 58A). Aromatic aldehydes bearing Biomolecular electron withdrawing (Cl, COOMe) at para-positions provided & higher yield of diacylated products in comparison of aldehydes having electron-releasing (Me, OMe) groups. - Naphthadehyde delivered the 92% yield of corresponding diacylated product. Moreover, aliphatic aldehyde such as cyclopropanecarboxaldehyde, cyclohexanecarboxaldehyde, heptaldehyde and isobutaraldehyde afforded the moderate

to good yield. Substituted carbazoles also delivered their Organic respective products in good yields. Interestingly, halogenated

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R2 R2 A acylation reaction, however pyridine and variousView derivatives Article Online O of pyridine were not very reactive andDOI: did 10.1039/D0OB01458C not furnish the Pd(OAc)2 (10 mol%) R1 H t R1 N H BuOOH (4 equiv) N O target product in good yield. The synthetic methodology could Dichloroethane N H N 1 80 oC, 8 h R O also be extended for the formal synthesis of natural alkaloid 20 examples, 27-94% (±) angustureine. The homolytic activation of C-H bond R1 = Ph, 4-ClPh, 3-ClPh, 4-BrPh, 2-BrPh, 4-FPh, 4-OMePh, 3-OMePh, 2,5-OMePh, 4-MePh, aldehyde using O2 as the oxidant led to the generation of acyl

4-CO2MePh, 4-COMePh, 4-CNPh, -naphthyl, cyclopropyl, cyclohexyl, n-hexyl, iPr, radical. On the basis of literature reports and the R2 = H, Me, COMe

B R2 experimental results obtained, a radical pathway was R2 O H R1 suggested for the reaction (Scheme 59B). The mechanistic R1 Pd(OAc) (10 mol%) 2 OMe tBuOOH (4 equiv) N studies suggested that the auto-oxidation of aldehyde lead to N H O Dichloroethane N o H N 80 C, 8 h the formation of acyl radical which reacted with the OMe protonated nitrogen heterocyclic moiety to form the radical 4 examples, 51-74% Manuscript

R1 = R2 = Br, I cation A, this cation formed the targeted acylated product C H O post oxidation. O III O N 2 Pd Recently in 2020 Lete and co-workers described Pd(II)- TBHP 2 Pd(OAc)2 Ph N OAc catalyzed C-2 acylation of pyrrole by aldehydes using 2- pyrimidine or 3-methyl-2-pyridine as directing groups using

Ac 92 N II O TBHP as oxidant. Using 2-pyrimidine as directing group 15 Pd N Ph N mono C-2 acylated derivatives of pyrrole were obtained in 14- 2 N O

2 Pd(OAc)2 72% yield along with their corresponding C-2, C-5 diacylated Accepted

2 AcOH 2 AcOH byproducts (<5-41% yield) (Scheme 60A). Aromatic aldehydes with having halogens (F, Cl, Br) on the para-position provided N III Ac 2 Pd(OAc) N O moderate to good yields of mono-acylayed products along 2 Pd N Ph O N 2 with minor <5-8% yield of diacylated product. Aryl aldehydes

bearing strong electron-withdrawing CF3, NO2 and CN groups III O N 2 Pd O provided solely monoacyalted product but in very poor yields N Ph O Ph N OAc O N O due to incompletion of the reaction. Although introduction of electron-releasing group on aryl ring of aldehyde provided Scheme 58: (A) & (B) Regioselective Pd-catalyzed direct ortho-mono and diacylation of good results but ortho-substituted aldehydes delivered lower Chemistry carbazole at C1 and C8 positions using aldehydes; (C) plausible reaction mchanism. Guin et al. attempted an aerobic radical approach for yield due to steric effect. -Naphthaldehyde resulted 51% synthesizing unsymmetrical heteroaryl ketones. The approach yield of C-2 acylated product along with 19% diacylated primarily involved cross-dehydrogenative coupling between product. To avoid the formation of byproduct authors tried 3- aldehydes and heteroaromatic bases in presence of molecular methyl-2-pyridine as directing group for the selective oxygen.91 A wide variety of nitrogen containing heterocyclic acylation of pyrrole and as was expected by authors all the Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. compounds were subjected to the aerobic radical acylation carried out reactions selectively delivered C-2 acylated process and delightfully, the acylated products could be product without detection of formation of diacylated successfully obtained in good yield showing excellent compound under the separately optimized. Aryl aldehydes regioselectivity at positions 2 and 4 (Scheme 59A). In a few with both electron-releasing as well as electron-withdrawing groups provided the corresponding derivatives in moderate to

cases, even the alkylated products could be synthesized. Apart Biomolecular from this, biologically relevant isoquinoline derivatives good yields. Heterocyclic aldehydes also provided the

containing sulphonamides could also be generated with corresponding acylated products in good yields resulting in & remarkable 99% selectivity. Several other nitrogen containing diheteroaryl ketones (Scheme 60B). heterocycles including quinazoline, substituted quinazoline, benzimidazole, thiazole, etc. also smoothly underwent the Organic

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R1 O R1 A O2 R1 H N TFA, EtOAc N B 100 oC R1 O N 37 examples, traces-77% H Manuscript

R1 = nPr, ethyl, nBu, ethylbenzene, n-pentanyl, iBu, iso-pentyanyl, cyclohexyl, cyclopropyl, CHEt , 2 N cyclohex-3-enyl, Ph, 4-OMePh, 4-BrPh H R2 = 4-Ph, 4-(4-Ph)Ph, 4-(4-OMe)Ph, 4-(2,4-F)Ph, 4-Me 1 -napthyl, 4-Br, 5-NHCOPh, 5-SO2NH(3-Cl-4-FPh), O R O A 5-(4-sulfonylpiperazin-1-yl)(phenyl)methanone, 4-(1-(4-sulfonyl-1,4-diazepan-1-yl)ethan-1-one), etc. R1 , O nPr O nPr HOO N N O2/HOO N nPr n N Pr N N N O O O2 HO /H O N Me N Ph 2 2 2 Accepted O nPr O Me 34% 50% 52% 43% 42% R1 H

N N N N H Me O OBn OBn S OBn O R1 n MeO MeO Me N Pr MeO i 45% n Bu Pr N N N 45% O 47% O 57% O Scheme 59: (A) Aerobic cross-dehydrogenative coupling between heterocyclic compounds and aldehdyes; (B) plausible reaction mechanism.

A 4. Miscellaneous Chemistry

N N N Pd(OAc)2 (10 mol%) N N N O O In 2012, Zhang and Hong reported the direct N-acylation of TBHP (4 equiv) O O N N N Ar H Piv(OH) (0.75 equiv) Ar Ar lactams, oxazolidinones and imidzolidinones using aldehydes toulene, 60 oC, 1.5-7 h Ar in the presence of Shvo’s catalyst in toluene as solvent.93 The 14 examples, 14-72% 10 examples, 5-41% best reaction conditions were defined as stirring a mixture of Ar = 4-MePh, 4-tBuPh, 4-FPh, 4-ClPh, 4-BrPh, 4-CNPh, 4-NO2Ph, 3,5-OMePh, 3,4,5-OMePh, 2,6-OMePh, lactam/oxazolidinone/imidzolidinone (0.25 mmol, 1 equiv.), Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. 2,4-OMePh, 4-CF3Ph, 3,5-CF3Ph, -naphthyl aldehyde (3.0 equiv) in the presence of Shvo’s catalyst (2.5 B mol%) in toluene (0.5 mL) as solvent at 100 oC for 24 h. In total N Pd(OAc)2 (10 mol%) N Me O TBHP (4 equiv) O Me 33 N-acylated derivatives of lactams, oxazolidinones and N N Ar H Piv(OH) (0.75 equiv) Ar imidzolidinones were synthesized in moderate to excellent toulene, 120 oC, 1-7 h

yields using several aromatic, aliphatic, heterocyclic and - Biomolecular 15 examples, 31-71%

Ar = 4-MePh, 4-tBuPh, 4-FPh, 4-ClPh, 4-BrPh, 4-CNPh, unsaturated aldehydes as acylating agents (Scheme 61A).

4-NO2Ph, 3,5-OMePh, 3,4,5-OMePh, 2,6-OMePh, & 4-OMePh, 4-OBnPh, 1-(tert-butyl)-1H-pyrrolyl, Based on the mechanism of Shvo’s catalyst, the authors 1-methyl-1H-pyrrolyl, furanyl proposed a plausible mechanism for this method as presented Scheme 60: Pd(II)-catalyzed C-2 acylation of pyrrole by aldehydes using (A) 2-pyrimidine or; (B) 3-methyl-2-pyridine as directing groups. in scheme 61B. This involves nucleophilic attack of lactam A to the carbonyl carbon of the activated aldehyde to form a hemiaminal B, which further oxidizes via -hydride elimination and undergoes proton transfer to produce the acylation product and ruthenium species C3. Organic

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A O O H O Shvo's catalyst (2.5%) O O O X X Ph NH N Ph + toluene, 100 oC, 24 h 1 R1 Ph n R H n Ph Ph n = 0, 1, 2 Ru Ph Ru Ph Ph X = NH, O & CH2 31 examples, 20-99% H OC CO OC CO R1= Ph, phenylethyl, styrenyl, pentyl, penta-1,3-dienyl, 1-phenylprop-1-en-2-yl, Shvo's catalyst (C )

1 Manuscript thiophenyl, 4-OMePh, 4-FPh, benzyl, H

O O O O O N N N N O O O O 80% 75% 61% 49%

O O O O O O O N N N N N N

O Accepted 63% 86% 46%

B [C2] O O OH O O C2 C3 R1 H OH O X X X X NH N N H N 1 R1 n n n R n n = 0, 1, 2 A B H O O Ph Ph Ph Ph Ph O Ph OH Ph Ph Chemistry Ph Ph Ph + Ph Ph Ru Ph Ru Ph Ru Ru H Ph OC OC H CO OC CO OC CO CO

C1 C2 C3 Scheme 61: (A) Direct N-acylation of lactams, oxazolidinones and imidzolidinones with aldehdyes using Shvo's catalyst; (B) proposed mechanism.

A copper catalyzed oxidative cross-coupling involving dual C- pathway for this protocol is described in scheme 62B. The

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. N/N-H functionalization for N-acylation of sulfoximines was proposed pathway involves the interaction of a Cu(II) catalyst disclosed by Wang et al. in 2013 by treating aldehydes with with sulfoximine to give intermediate A. This intermediate A sulfoximines in the presence of TBHP as oxidant under mild reacts with an acyl radical generated from the aldehyde in the reaction conditions (Scheme 62A).94 A set of 14 derivatives of presence of TBHP. Subsequently, an electron transfer N-acylsulfoximines was prepared with good functional group processes results in the construction of N-acylsulfoximine and tolerance. In addition to S,S-methylphenyl sulfoximine, the a Cu(I) species. The later re-oxidizes to Cu(II) in the presence Biomolecular

reaction proceeded smoothly with S,S-dimethyl and S,S- of TBHP. & tetramethylenesulfoximines also and afforded their respective products in excellent yields. Also, benzaldehyde bearing a nitro group at the para- and meta-position furnished the targeted compounds in excellent yields. Not only a nitro group but also other electron-withdrawing groups such as F, Cl and electron-releasing groups such as methoxy, alkyl, etc.

were well tolerated, delivering various N-benzoylsulfoximines Organic in good to excellent yields. A redox process based plausible

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A CuBr (mol%) O O O O A TBHP (2.0 equiv) 2 View Article Online 2 R + R S NH S O DOI: 10.1039/D0OB01458C 1 o 1 PivOH (2.0 equiv) R H MeCN, 80 C R3 N R R3 + X TBHP (2.0 equiv) 12 h R1 H 14 examples, 72-95% X CH3CN O O R2 Ar, 120 oC, 48 h R2 1 S R = Ph, 4-NO2Ph, 3-NO2Ph, 4-PhPh, X= C(COOMe) , TsN & O 1 N 4-OMePh, 4-ClPh, 4-FPh, 4- -BuPh, 2 R t O -naphtyl, i-Pr, COPh 33 examples, traces-70% O2N 2 3 85% R /R = Me/Ph, Me/Me R1= Ph, 4-MePh, 4-ClPh, 4-BrPh, 3-MePh, 3-OMePh, 3-ClPh, 3-BrPh, 2-MePh, 2-OMePh, 2-ClPh, 2-BrPh, 3,4-MePh, 2,4-ClPh, benzo[d][1,3]dioxolyl, thiophenyl, i-Pr, i-Bu, B O O 2 TBHP R2= H, 8-Me, 7-Me, 7-OMe, 7-CO Me, 7-CN, 7-Br, R Cu(l) Cu(ll) 2 O 2 S R 7-Cl, 7-Ph, 5-OMe, 5-F, etc. 1 R3 N R S R3 NH B tBuOOH tBuO + OH R2 O O TBHP O S tBuOOH 3 R O HN Cu(ll)Ln R1 H 1 Cu(ll)Ln R 1 MeOOC A 1 R O MeOOC R H MeOOC MeOOC O Manuscript Scheme 62: (A) Cu(II)-catalyzed acylation of sulfoximines using t BuOH + H2O aldehydes; (B) proposed mechanism. R1 A MeOOC R1 O MeOOC B In 2014, Luo and Liang developed a metal-free one-pot

cascade cyclization of 1,6-enynes with aldehydes involving H tBuOOH MeOOC MeOOC 2 2 2 3 MeOOC simultaneous one C(sp )-C(sp ) and two C(sp )-C(sp ) bond MeOOC

t 1 formation for the synthesis of carbonylated tricyclic fluorene 1 BuO + H2O R R O 95 O C derivatives by using PivOH and TBHP. The reaction Scheme 63: (A) Metal-free one-pot cascade cyclization of 1,6-enynes with aldehydes; (B) conditions were optimized as the reaction of a 1,6-enyne (0.2 plausible reaction mechanism. Accepted mmol) with an aldehyde (1.0 mmol) in the presence of the To understand the mechanism, kinetic isotope effect and free- oxidant TBHP (0.4 mmol, 70% aqueous solution), the additive radical quenching experiments were examined. No kinetic PivOH (0.4 mmol) in acetonitrile as solvent (1 mL) at 120 oC for isotope effect (kH/kD = 1.0) was found by the outcome of 48 h under argon atmosphere. The developed reaction intramolecular and intermolecular reactions under standard conditions were initially examined for exploitation of reaction conditions. This ultimately revealed a free-radical or aldehydes in this cascade oxidative cyclization process. SEAR route for this reaction. Also, inhibition of the reaction in Various aromatic aldehydes containing electron-releasing and the presence of 4 equiv of TEMPO clearly indicated that the electron-withdrawing groups participated in this reaction to reaction proceeds via a free-radical route. A large kinetic

give the targeted fluorene derivatives in good yields Chemistry isotope effect (KIE, kH/kD = 9.1) value for the 1:1 mixture of regardless the positions of substituents on the aryl ring of the benzaldehyde and [D6]-benzaldehyde implied that cleavage of benzaldehydes (Scheme 63A). Aliphatic aldehydes were not the carbonyl C-H bond is the rate-determining step for this suited in this transformation and only traces of the products conversion. Depending on these observations and previous could be obtained. Remarkably, benzo[d][1,3]dioxole-5- reports in this field,96 a plausible mechanism was proposed carbaldehyde and thiophene-2-carboxyaldehyde could also (Scheme 63B). Initially, homolytic cleavage of TBHP under

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. undergo the reaction giving the products in 45% and 35% heating conditions generated alkyloxy and hydroxyl radicals. yields, respectively. Delighted by these promising results, the These radicals capture a hydrogen atom from benzaldehyde scope of 1,6-enyne substrates was examined with to form an acyl radical, and successive attack of this acyl benzaldehyde and the reaction progressed efficiently in most radical at the CC bond of the enyne afford the radical cases to give the desired products in moderate to good yields intermediate A. Next, an intramolecular cyclization process (Scheme 63A). 1,6-Enynes substituted with electron-releasing generates a tertiary carbon radical B, which subsequently by Biomolecular alkyl or alkoxy groups at the ortho, meta or para-position or another intramolecular cyclization with an aryl ring give rise & containing either halogen or an electron-withdrawing COOMe to radical intermediate C. Lastly, direct oxidation and or CN group at the para-position were suitable for this deprotonation of intermediate C by TBHP furnishes the final reaction affording the corresponding carbonylated fluorenes. product. Tosylamides also react with benzaldehyde to give products in moderate yield, whereas only trace amounts of the product Fuwei Li and his team in 2014 demonstrated a KI-catalyzed (9,9-dimethyl-1,3,9,9a-tetrahydroindeno[2,1-c]pyran-4- oxidative cross-coupling of C-N and N-H bonds between azoles and aromatic aldehydes for the direct N-acylation of azoles in

yl)(phenyl)methanonewas obtained from the corresponding Organic 97 enyne substrate. the presence of TBHP as oxidant. Various derivatives of azole

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ARTICLE Organic & Biomolecular Chemistry

(0.3 mmol) were reacted with aldehydes (0.45 mmol) in the To investigate the reaction mechanism, control Viewexperiments Article Online presence of KI (0.06 mmol) as standard catalyst using TBHP were performed in the presence of free-radicalDOI: 10.1039/D0OB01458C scavengers (0.9 mmol) as ideal oxidant in dichloroethane (DCE) as solvent like TEMPO and 1,1-diphenylethylene. These experiments at 100 oC for 12 h. A total 28 derivatives were prepared in suggested the formation of an acyl radical and a free-radical moderate to excellent yields irrespective of the positions and pathway for this conversion. Based on these results, two nature of the substituents on the azoles as well as on the possible pathways were proposed as shown in scheme 64C. It aldehydes (Scheme 64A). When the scope of aldehydes was was hypothesized that the tert-butoxyl and tert-butylperoxy examined with pyrazoles, para-substituted benzaldehydes radicals are generated initially in the catalytic system, which containing electron-donating (OMe, tBu) groups and electron- could abstract a hydrogen atom from the aldehyde to withdrawing (Cl, Br, CN) groups reacted effectively with 3- generate the acyl radical. This acyl radical on reaction with the phenyl pyrazole and delivered the products in 57% to 95% azole give the acyl azole radical anion A. Subsequently, radical yield. Ortho-methoxybenzaldehydes resulted inferior yield in anion A by losing an electron via a SET process in the presence Manuscript comparison to para-methoxybenzaldehydes. - of the tert-butoxyl or tert-butylperoxy radical afforded the naphthaldehdyde and thiophene-2-carbaldehdydes were also desired N-acyl azoles (Path A). In path B, it is represented that found suitable for this transformation leading to 90% and 72% the tert-butoxyl and tert-butylperoxy could capture a single yield of the products, respectively. Encouraged by these electron from the azoles leading to an azole cation species B, findings, the authors further explored the scope of other which upon deprotonation with the help of tert-bytoxyl anion azoles such as benzimidazole, benzotriazole and indazole with could convert to azole radical C. Finally, the coupling between various substituted aromatic aldehydes. Benzaldehydes with acyl radical and azole radical cation B or azole radical C

electron-releasing groups provided products in 85% to 98% provided the desired product. Accepted yield whereas electron-withdrawing substituents afforded In 2015, Singh and co-workers for the first time developed a yields of 24% to 78% upon reaction with benzimidazole. mild oxidative amidation process of aldehydes using Surprisingly, benzotriazole reacted only with ortho- acetanilide as amine component in the presence of copper substituted benzaldehydes and no product formation was catalyst and TBHP as oxidant.98 Acetanilide and benzaldehyde observed with para-substituted benzaldehydes. Furthermore, were taken as model reactants and the reaction was carried indazole upon treatment with para-bromobenzaldehyde gave out using NBS catalyst and TBHP as oxidant in acetonitrile at 44% yield. 100oC, and 55% yield of benzanilide was obtained. Chemistry C t t A KI (20 mol%) R1 BuOOH BuO OH O TBHP (3 equiv) N + NH R1 H DCE, 100 oC R2 N O R2 N 1/ I 13 examples, 31-95% I 2 2 R1= Ph, 4-OMePh, 4-t-BuPh, 4-BrPh, 4-ClPh, 4-CNPh, 2-OMePh, 3-FPh, 3,5-OMePh, thiophenyl, -naphthyl H2O tBuOO tBuOOH OH 2 R = H, Ph Path A Y X B O X X KI (20 mol%) NH X 1 1 O tBuO O Y R t Y X R Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. + Y TBHP (3 equiv) Y BuO 1 N N R H N N H 1 or R1 or o R H O O DCE, 100 C 1 tBuOO tBuOO X=N, Y= C R A O X=N, Y= N Path B O X=C, Y= N 13 derivatives, 24-98% X X X 1 Y tBuO Y Y R1 Y X R R1=Ph, 4-BrPh, 4-CNPh, 2-BrPh, 2-OMePh, NH NH or N N or 3-NO2Ph, 3,4-OMePh, -naphthyl, t O BuOO B C thiophenyl Biomolecular Scheme 64: (A) & (B) KI-catalyzed oxidative cross-coupling of C-N and N-H bonds for N-acylation of azoles using aromatic aldehydes; (C) plausible reaction mechanism. & To improve the product yield, several other catalysts, oxidants various substituted acetanilides and aldehydes, and finally a and solvents were screened. Finally, by several combinations library of 24 benzanilide derivatives was prepared (Scheme and permutations, the reaction conditions were optimized by 65A). Acetanilides as well as benzaldehydes containing stirring of a mixture of acetanilide (0.5 mmol), benzaldehyde electron-releasing and electron-withdrawing groups such as

(1 mmol) in the presence of CuCl2.2H2O (10 mol%) catalyst Me, OMe, Cl, Br, NO2, CN, etc. underwent the reaction using TBHP (2 equivalents) as oxidant in DCE as solvent at 100 smoothly delivering the products in moderate to good yields.

oC for 24 h. With these optimized reaction conditions, the Thiopene-2-carbaldehyde gave the product in 52% yield. Organic scope and versatility of the reaction was examined using However other heterocyclic aldehydes such as furfural and

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indole-3-carboxyaldehyde showed no product formation respectively. Based on literature reports and experiments,View Article Online a because of their decomposition in the presence of TBHP. plausible reaction mechanism was proposedDOI: 10.1039/D0OB01458C as shown in Aliphatic aldehydes such as heptanal and cinnamaldehyde scheme 65B. afforded the corresponding products in 64% and 76% yield,

A B O O O O CuCl2 2H2O R2 TBHP R2 NH + 1 R1 H N Me R N H H O 24 examples, 0-82% N R1= Ph, 4-MePh, 4-OMePh, 4-ClPh, Cu(ll)Ln 4-NO Ph, 3-ClPh, 3-BrPh, 2-BrPh, Cu(ll)Ln 2 A 2,4-ClPh, thiophenyl, furanyl, styrenyl, O H TBHP hexyl, 1H-indol-3-yl N 2 R = Ph, 4-MePh, 4-ClPh, 4-NO2Ph, Cu(l)Ln H R 4-CNPh, 3-CF3Ph, 4-(COMe)Ph, O O TBHP

3-ClPh, 2-BrPh, 3-MePh, pyridin-2-yl, Manuscript cyclohexyl N O O

R

B

Scheme 65: (A) Cu-catalyzed oxidative amidation of aldehydes using acetanilide; (B) plausible reaction mechanism.

In the same year (2015), Achar et al. executed a metal-free In 2017, Cijil Raju and co-workers reported a Cu-catalyzed oxidative cross-coupling for the amidation of aldehydes with double C-H/N-H activation protocol between

N-chloramines in the presence of TBAI (tetrabutylammonium sulfonimidamides and aldehydes affording a diversity of N- Accepted iodide) in combination with TBHP under neat conditions at acyl sulfonimidamides in low to moderate yields (Scheme 50oC or ball-milling conditions at room temperature (Scheme 67).100 In this typical procedure, a mixture of 66A).99 Using this protocol, 19 amide derivatives were sulfonimidamides (4.0 equiv.), aldehydes (1.0 equiv.) in the obtained in good yields by treating aromatic aldehydes, presence of CuBr (5 mol%) as catalyst and TBHP (2.0 heteroaromatic aldehydes and aliphatic aldehydes with equivalent) as oxidant in acetonitrile was stirred at 82 oC for 2 primary and secondary N-chloramines. Aryl aldehydes having h. Employing these optimal conditions, 26 different N-acyl electron-donating Me and OMe substituents give 84% and sulfonimidamides were prepared in 18-56% yields, starting 82% yield of the respective amides. Furthermore, the from aromatic, heterocyclic and aliphatic aldehydes and Chemistry presence of electron-withdrawing substituents such as F, Cl, various sulfonimidamides. Various benzaldehydes with

Br, CF3, NO2, etc. on the aryl system of aromatic aldehydes was electron-donating and electron-withdrawing substituents in found to be competent for this amidation reaction. different positions display identical ease towards the N- Thiophene-2-carbaldehyde provided 76% yield of the product, acylation of sulfonimidamides. Both mono- and di-substituted whereas in case of aliphatic aldehydes, inferior yields (53%- aromatic aldehydes worked well under these developed 64%) were obtained. Similarly, various N-chloramine reaction conditions. Interestingly, the presence of the bulky Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. derivatives such as N-chloro-1-phenylmethanamine, N- tBu group at the C-3 and C-5 position of the aryl aldehyde does chloro-N-methyl-1-phenylmethanamine, N-benzyl-N-chloro- not inhibit the product formation and 47% yield was obtained. 1-phenylmethanamine etc. also reacted smoothly and The scope of the reaction was not limited only to aryl enabled good product yields. To get insight into the reaction aldehydes as hetero-aromatic and aliphatic aldehydes were

mechanism, control experiments were performed under neat also found feasible for this transformation. The modifications Biomolecular conditions (Scheme 66B). Based on the results of these in the aryl system of the sulfonimidamide moiety were well

experiments, a plausible reaction mechanism was proposed tolerated and replacement of the piperidine part with & as shown in scheme 66C. morpholine and pyrrolidine was also found to be compatible and yielded the corresponding products smoothly. Organic

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A O R2 TBAI (20 mol%) O N TBHP (2 equiv) R2 R1 H Cl R3 R1 N neat, 50 oC, 1.5 h R3 19 examples, 53-84%

R1= Ph, 4-OMePh, 4-MePh, 4-ClPh, 4-CF Ph, 3 C 4-BrPh, 4-NO2Ph, 4-FPh, 3-Br-4-OMePh, O R2 TBAI O 3-BrPh, 3-NO2Ph, 3,4,5-OMePh, 3,4-OAcPh, TBHP R2 thiophenyl, nonanyl, cyclohexyl N 1 1 3 R N HCl R H Cl R Manuscript R2/R3= benzyl, Me, H R3

B H N t 2 t BuOH OH BuO OH 1/2 I2 O (i) O

H Cl 0% N N (TBAI) H (TBHP) t H 73% H2O BuOO F t F BuOOH I

t t Ph BuOO or BuO 2 t t R BuOO or BuO 2 HN O O R N N Ph Cl R3 3 (ii) O Ph R1 H R1 R O tBuOOCl or tBuOCl t or t 11% BuOOH BuOH Accepted Ph N H O Cl N 73% 2 Ph R Ph R N R3 (iii) O O N TBAI (20 mol%) O H N TBHP (2 equiv) O neat, 50 oC, 1.5 h Cl Cl TEMPO

Scheme 66: (A) Metal-free oxidative cross-coupling for the amidation of aldehydes using N-chloramines; (B) control experiments; (C) plausible reaction mechanism.

O

catalyst, t-BuOK (0.8 mmol)/NaH (1.2 mmol) base in THF as Chemistry H O O N R1 o N CuBr (5 mol%) solvent under N2 atmosphere at 25 C followed by quenching O S tBuOOH (2.0 equiv) S N N using 1M HCl aqueous solution. The scope of the primary H R1 MeCN, 82 oC 2 h R2 R2 amines with aldehydes was investigated by synthesizing 24 N- 25 derivatives, 18-54% acylated derivatives of amines in high yields. Aryl aldehydes N N N N R1= 4-MePh, 4-BrPh, 4-ClPh, 4-FPh, = bearing substituents such as F, Cl, OMe and NO2 at different 4-NO2Ph, 3-ClPh, 3,4-ClPh, 3,4-FPh, O 3,5-t-BuPh, 3-NO2Ph, furanyl, thiophenyl,

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. positions (ortho-, meta- and para-) of the aryl ring participated n-Pr, ethyl 2 R = H, 4-Me, 4-CF3 in the reaction with tosylamide to give the respective N- Scheme 67: Cu-catalyzed double C-H/N-H activation between sulfonimidamides and aldehydes for the synthesis of N-acyl sulfonimidamides. tosylcarboxamindes in high yields. Interestingly, thiophene-2- carbaldehyde and 2-naphthaldehyde provided the respective Later in 2017, Zheng and Ma published a direct oxidative N- imides in 87% and 91% yields with these newly developed acylation reaction of primary amines with conditions. Moreover unsaturated aldehydes including Biomolecular aryl/unsaturated aldehydes in the presence of the enals and ynals were well suited for this direct N-acylation azolium salt of an N-heterocyclic carbene and base such as protocol of tosylamide and conjugated ynals having aliphatic & t BuOK or NaH using 3,3ʹ,5,5ʹ-tetra-tert-butyldiphenoquinone or aromatic substituents exhibited a wide scope resulting in o 101 (DPQ) as oxidant at 25 C (Scheme 68). This methodology 71-87% yields of the products. Unfortunately, alkylated provided a proficient approach for the synthesis of N- aldehydes were found inactive under the current reaction sulfonylcarboxamides, N-sulfinylcarboxamides and conditions and could not afford the imide products probable dicarboxyimides in good yields. The reactions were carried out due to competing enolization of the aldehyde substrate. by reacting a mixture of the corresponding amine (0.4 mmol) Organic and aldehyde (0.6 mmol) in the presence of NHC (10 mol%) To expand the synthetic utility of this methodology, other amide substrates were examined. Electron-rich

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(unsubstituted) as well as electron-poor (p-NO2 and p-Cl In the meantime, Hu and co-workers developedView an Article efficient Online DOI: 10.1039/D0OB01458C substituted) aryl sulfonamides upon reaction with 4- PhI(OAc)2-promoted double acylation (N- and O-acylation) of chlorobenzaldehyde delivered the corresponding products in hydroxylamines with aldehydes at room temperature in acetic 93-96% yields. Besides, methanesulfonamide was also acid for the synthesis of N-acetoxy-N-arylamides in good to witnessed as a competent reaction partner given that 92% excellent yields.102 The acylation of N-atoms in yield of the product was obtained. Additionally, benzamide hydroxylamines are due to the acyl group of aldehydes and its p-chloro and p-nitro derivatives could also be whereas the O-atoms get acylated by the acetyl group of

employed for the formation of dicarboxyamides using a PhI(OAc)2. This transformation exhibited great substrate stronger base NaH (3.0 equiv.) instead of tBuOK, due to the scope under the optimized reaction conditions. Initially, the inferior acidity of carboxamides compared with sulfonamides. effect of aromatic aldehydes was explored with N- (S)-tert-butylsulfinamide (99% ee) suited efficiently in this phenylhydroxylamine and all the selected aryl aldehydes protocol and yielded the (S)-tert-butylsulfinamide-4- could give the desired products regardless of the nature Manuscript chlorobenzamide in 81% yield with almost complete retention (electron-releasing or electron-donating) of the substituents (98% ee) of configuration (Scheme 68A). present on the aromatic ring. However, in some cases, the positions of the substituents on the aryl ring of the A 10 mol% C O O DPQ (1.5 equiv) O O benzaldehydes were found to influence the reaction yield. For t X BuOK or NaH X 1 + 2 1 example, m-nitrobenzaldehyde delivered 85% yield whereas R H R NH2 o R2 N R THF, N2, 25 C H X= C, SO & S p-nitrobenzaldehyde resulted in 73% yield but unfortunately 20 examples, 71-97% no product formation took place with o-nitrobenzaldehyde. 1 R = Ph, 4-ClPh, 4-FPh, 3-OMePh, 3-NO2Ph, N Cl The 2-furaldehyde and pyridine-2-carboxaldehdye offered Accepted N thiophenyl, -naphthyl, styrenyl, hept-1-ynyl, C = N MeS 1-ethynylcyclohex-1-ene, ethynylbenzene their respective products in good yields; on the other hand, no 2 R = Ph, 4-MePh, 3-NO2Ph, 4-ClPh, product formation was observed with aliphatic aldehydes Me, 4-NO2Ph, t-Bu

B O O (Scheme 69). R1 S N R N A O AcO OAc H N N Mes R O I O O CH3COOH O O A R2NHOH R1 N R1 H + + Fragmentation N2, rt, 1 h R1 S O R2 O

HN O OH 35 examples, 0-96% N N 1 R R R = Ph, 2-MePh, 3-MePh, 4-MePh, 3-OMePh, 4-OMePh, Chemistry 2-ClPh, 3-ClPh, 4-ClPh, 2-NO2Ph, 3-NO2Ph, 4-NO2Ph, N N N N D 4-CNPh, furanyl, pyridinyl, propyl, 4-CF3Ph Mes Mes 2 B R = Ph, Me, t-Bu, 2-MePh, 3-MePh, 4-MePh, 2-ClPh, 3-ClPh, 4-ClPh, 4-BrPh, 4-AcPh, 4-(CO C H )Ph 1,2-Addition 2 2 5 Oxidation B Ph O AcO OAc I O O DPQ I -H N R O Ph O O R1 S NH R1 S NH O 2 N Me N N PhNHOH N

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. + Ph O O R1 H Ph O Mes 1 A' C R1 R B Scheme 68: (A) N-acylation reaction of primary amines with aryl/- A unsaturated aldehydes using azolium salt of an N-heterocyclic carbene; -PhI (B) plausible reaction mechanism. CH3COO

The postulated catalytic cycle for this transformation is O OAc Me

O Biomolecular 1 O H N presented in scheme 68B. The pathway initially involved the N R Ph Ph N O R1 Ph O Me formation of Breslow intermediate B through nucleophilic O R1 & -CH3COOH O addition of in situ generated carbene A to aldehyde. The D C

intermediate B oxidized to form acylazolium species C upon Scheme 69: (A) PhI(OAc)2-promoted double acylation (N- and O-acylation) treatment with DPQ. Then attack of the deprotonated amide of hydroxylamines with aldehydes; (B) plausible reaction mechanism. compound A' probably via 1,2-adduct D, on azolium Similarly, the applicability of various N-aromatic intermediate C, followed by a fragmentation sequence gave hydroxylamines bearing an electron-rich methyl group or the final compound along with the carbene catalyst A. electron-poor chloro, bromo, acetyl or ester group reacted with benzaldehyde, and the corresponding products were Organic obtained in 45-75% yields. However, no product could be

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ARTICLE Organic & Biomolecular Chemistry

obtained with aliphatic hydroxylamines such as N- formation and provided the final View compound. Article Online DOI: 10.1039/D0OB01458CO methylhydroxylamine and N-(t-butyl) hydroxylamine. The A O O O R1 compatibility of the simultaneous in present substituents on O Pd(OAc)2 (5 mol%) TBHP (5 mmol) N R1 H aromatic aldehydes and aromatic hydroxylamine was also N 1,4-dioxane o O exploited. The aromatic aldehydes delivered a higher product 120 C, 18 h 18 examples, 22-79% yield when electron-withdrawing groups were present as R1= Ph, 2-FPh, 2-ClPh, 2-BrPh, 4-MePh, 4-OMePh, 4-FPh, 4-ClPh, 4-BrPh, 3,4-MePh, 3,4-OMePh, substituents, compared to aromatic aldehydes having 3-ClPh, 2,4-FPh, 2,6-FPh, 2-F-4-ClPh, 2-F-4-BrPh, cyclohexyl, i-Pr electron-withdrawing groups. On the other hand, aromatic B O

hydroxylamines with electron-donating groups on their O

phenyl rings resulted in higher product yields than those with N

Pd(OAc)2 tBuOOH electron-withdrawing groups with the same aldehydes AcOH (Scheme 69A). A plausible mechanism for this reaction is O Cyclopalladation

O Manuscript Pd(0) O shown in scheme 69B. At the beginning, the aldehyde reacted O N Reductive N with hydroxylamine to form a nitrone intermediate A. Then a t BuOOH O Elimination Pd O AcO ligand exchange process took place between nitrone A and A O O PhI(OAc)2 to produce intermediate B, which on intramolecular O C N rearrangement produced another intermediate C. The Pd N O deprotonation of intermediate C by an acetate resulted in O O D B intermediate D, which on subsequent migration of the acyl tBuO + OH

Migration of Accepted group and isomerization gave the final product. Pd(OAc) phenyl ring 2 O O tBuOH In 2018, our lab disclosed a radical-induced Pd-catalysed tBuOOH O H O approach for the direct functionalization of 2-phenyl-4H- O N N 103 benzo[d][1,3]oxazin-4-ones with aldehydes. The reaction O O proceeded through the formation of the o-acylated 2-phenyl- E 4H-benzo[d][1,3]oxazin-4-one intermediate to give 6a- Scheme 70: (A) Pd-catalyzed direct functionalization of 2-phenyl-4H-benzo[d][1,3] oxazin-4-ones with aldehydes; (B) plausible reaction mechanism. phenyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)- diones in the presence of the TBHP oxidant. Various aryl Segundo and Correa in 2019 reported Pd-catalyzed oxidative coupling between phenylalanine based peptides with aldehydes with electron-releasing groups (Me, OMe) and Chemistry electron-withdrawing groups (F, Cl, Br, etc.) reacted smoothly aldehydes for site-selective C(sp2)-H acylation using DCP with 2-phenyl-4H-benzo[d][1,3]oxazin-4-one in the presence (dicumyl peroxide) as oxidizing agent and Ag2CO3 as 104 of Pd(OAc)2 (5 mol%) as catalyst using TBHP (5 mmol) oxidant additive. With the optimized reaction conditions the scope in 1,4-dioxane as solvent at 120 oC for 18 h to afford 19 of C(sp2)-H acylation of phenylalanine derivatives was derivatives in 21-79% yields (Scheme 70A). Aliphatic investigated by coupling with a wide variety of aldehydes and the desired products could be obtained in moderate to Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. aldehydes such as cyclohexanecarboxaldehyde and isobutyraldehyde delivered the corresponding products in excellent yields (Scheme 71A). Aryl aldehydes having 48% and 33% yields, respectively. A plausible reaction electron-releasing (Me, OMe, Et2N, 2,3-dihydrofuryl) groups mechanism was proposed based on control experiments and resulted the mixture of mono- and di-acylated compounds, previous literature reports (Scheme 70B). Initially, 2-phenyl- which could be easily separated. 2,4,6-

4H-benzo[d][1,3]oxazin-4-one underwent the ortho- trimethoxybenzaldehdye delivered only di-acylated Biomolecular

palladation reaction with Pd(OAc)2 to form complex A and by- compound in 67% yield. Similarly, p-hydroxybenzaldehyde, 2- product AcOH. At the same time, an acyl radical is formed chlorobenzaldehyde and -naphthaldehyde delivered the & from the aldehyde by action of TBHP. A subsequent reaction mono-acylated products in 63%, 45% and 54% yield, between complex A and acyl radical promoted the formation respectively. Heterocyclic and aliphatic aldehydes were also of complex B, which goes through a reductive elimination smoothly reacted to give the corresponding products in good process to give o-acylated intermediate C. In the next step, the yield. Moreover, substituted phenylalanine derivatives also o-acylated intermediate underwent an aryl ring migration in afforded the monoacylated compounds in moderate to good the presence of TBHP and gave intermediate D followed by yields. To expand the generality of the protocol the scope of Organic biradical intermediate E. Biradical E undertook C-N bond phenylalanine based di, tri and penta-peptides was also

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explored with optimized reaction conditions and targeted reports authors have proposed a mechanismView Article for Online this products was obtained in good to excellent yield irrespective transformation (Scheme 71C). DOI: 10.1039/D0OB01458C of the effect of nature of side chains present in peptide chain (Scheme 71B). Based on control experiments and literature

O O A H

R2 O 1 1 Pd(OAc)2 (10 mol%) R R R2 R2 + H R1 DCP (2 equiv) PA Ag CO (2 equiv) N CO2Me 2 3 PA 1 H o O R DMF (0.25 M) 100 C N CO2Me PA H Ar, 16 h N CO2Me H OH 17 examples, 30-81% O R1 = 4-MePh, 4-OMePh, 4-NEt2Ph, 2-OMePh, OMe 4-OHPh, 2-ClPh, 2,4,6-OMePh, ethyl, n-hexyl, 2,3-dihydrobenzofuranyl, 3-indolyl, thiophenyl O Manuscript R = 4-Cl, 3-F MeN O 2 BnN PA N PA = Picolinamide N CO2Me N HN H CO2Me F 50% 72% B H O O

O 1 R1 Pd(OAc)2 (10 mol%) R + H R1 DCP (2 equiv) + PA Ag2CO3 (2 equiv) O R1 DMF (0.25 M) 100 oC * PA

Ar, 16 h PA Accepted

O O O O

R1 Me MeO Me MeS H H H H PA N CO Me 2 PA N CO2Me PA N CO2Me PA N CO2Me N N N N H H H H O O O O Ph Ph 44% 33% 52% 57% from PA-Phe-Leu-OMe from PA-Phe-Leu-OMe from PA-Phe-Phe-OMe from PA-Phe-Phe-OMe

O CO2Me CO2Me N HN PA N TMB TMB O Chemistry Ar TMB O O O H H O HN PA N CO2Me PA N N N OH Et2N H Ar = H O O CO2Me O N Ph NBn 43% N O TMB 31% 62% from PA-Phe-Leu-OMe from PA-Phe-The-OMe from PA-Phe-Pro-OMe 39% from triazole-Phe-Pro-OMe O O O

TMB TMB

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. O O O H H H H PA N PA N N N CO Bn PA N N CO2Me N N CO2Me 2 N N H H H H H H O O O O Ph Ph 32% 48% 52% from PA-Phe-Ala-Val-OBn from PA-Phe-Ala-Leu-OMe from PA-Phe-Phe-Val-Phe-OMe O O

Ar TMB O O Biomolecular H H Et2N PA N N O N N N CO2Me PA O H H H N PA O N O & O O H H Ph Ph N N N Ph N N N Ph 31% H H from PA-Phe-Phe-Leu-Phe-lle-OMe O O 70% O N CO2Me CO Me H N 2 from PA-Phe-Pro-Val-Pro-Phe-OMe 78% H from PA-Phe-Pro-Val-Pro-Phe-OMe Scheme 71: Pd-catalyzed oxidative coupling between phenylalanine based peptides with aldehydes for site-selective C(sp2)-H acylation. Organic

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ARTICLE

O post-functionalization of drug molecules and natural products Ph HN and transient directing group mediated acylations. Research N Pd(OAc)2 CO2Me in the fields of visible light mediated synthesis and continuous reductive AcOH flow synthesis are still in their infancy. There is a room for elimination coordination O further improvements via the use of alternative energy CO2Me O

N Ph sources like ultrasound and microwaves that have also played Manuscript N lV N Pd N a crucial role in achieving the green chemistry objectives in Pd CO2Me O organic synthesis via enhancing the efficiency and rapidity of R OAc

cyclopalladation organic reactions. oxidation Me Me O CO2Me Ph O Nevertheless, we anticipate that in the upcoming years, the O O N ll AcOH limitations and scope of these protocols shall be duly N Pd R R H addressed, fuelling more interest in this area. This review has Me Me

been an attempt to propagate the key findings on the use of Accepted Ph OH less toxic and stable aldehyde motifs for the construction of a Scheme 71(C): Plausible reaction mechanism for Pd-catalyzed oxidative coupling between phenylalanine based peptides with aldehydes. plethora of keto compounds; few examples discussed herein are quite motivating from the viewpoint of armouring the Conclusions and Future Perspectives organic chemists with sustainable synthetic methodologies which is the pre-requisite of the hour. Over the past decades, aldehydes have emerged as excellent acylation surrogates for the direct forging of acylated Conflicts of interest compounds containing keto motifs. Consequently, there has There are no conflicts to declare. been a profitable interplay of acylation and C-H activation for Chemistry gaining a ready access to these bioactive molecules with Acknowledgements enhanced selectivity and improved atom economy under The authors gratefully acknowledge their respective ambient reaction conditions. Also, considerable attention has universities/research organizations in particular, SRM been devoted by researchers to the exploration of the University, Sonepat; Department of Chemistry, University of mechanisms behind these fascinating transformations, Delhi and Peoples’ Friendship University of Russia (RUDN

Published on 07 September 2020. Downloaded by Karolinska Institutet University Library 9/7/2020 12:45:51 PM. opening new horizons for further research in this area. There University) Miklukho-Maklaya, Moscow, Russia for extending all have been massive breakthroughs with more than 100 possible support for furtherance of research. research articles published in high impact factor journals Notes and references involving the selective acylation of arenes, heteroarenes and 1. M. D. Barratt, J. V. Castell, M. A. Miranda and J. J. alkyls (sp3, sp2 and sp) C-H bonds. Interestingly, this strategy Langowski, J. Photoch. Photbio. B, 2000, 58, 54-61. is witnessing expanded applications in the fields of Biomolecular 2. E. A. Smith, J. G. Marshall, S. S. Selph, D. R Barker and photocatalysis as well as flow chemistry. The pivotal findings C. M. Sedgley, J. Endod., 2017, 43, 7-15. & from various studies clearly delineate prospects of large-scale 3. V. Agarwal, M. Bajpai and A. Sharma, Recent Pat. industrial synthesis for obtaining diverse heterocyclic Drug Deliv. Formul., 2018, 12, 40-52. compounds. 4. J. Zheng, Drug Metab. Pharmacokinet., 2018, 33, S70. Although tremendous accomplishments in this field have 5. S. C. Zimmermann, T. Tichý, J. Vávra, R. P. Dash, C. E. been achieved to change the landscape of organic synthesis, Slusher, A. J. Gadiano, Y. Wu, A. Jančařík, L. Tenora, yet a lot of work remains to be accomplished. Particularly, L. Monincová, E. Prchalová, G. J. Riggins, P. Majer, B. Organic future directions in this research area should focus on the S. Slusher and R. Rais, J. Med. Chem., 2018, 61, 3918- 3929.

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85. Y. Shin, S. Sharma, N. K. Mishra, S. Han, J. Park, H. 97. J. Zhao, P. Li, C. Xia and F. Li, Chem. Commun.,View Article 2014, Online Oh, J. Ha, H. Yoo, Y. H. Jung and I. S. Kim., Adv. Synth. 50, 4751-4754. DOI: 10.1039/D0OB01458C Catal. 2014, 357, 594-600. 98. S. Kumar, R. Vanjari, T. Guntreddi and K. N. Singh, 86. P. Cheng, Z. Qing, S. Liu, W. Liu, H. Xie and J. Zeng, RSC Adv., 2015, 5, 9920-9924. Tetrahedron Lett., 2014, 55, 6647-6651. 99. T. K. Achar and P. Mal., J. Org. Chem., 2015, 80, 666- 87. (a) J. W. Yuan, Q. Y. Yin, L. R. Yang, W. P. Mai, P. Mao, 672. Y. M. Xiao, and L. B. Qu, RSC Adv., 2015, 5, 88258- 100.G. C. Nandi and C. Raju, Org. Biomol. Chem., 2017, 15, 88265; (b) W. Zhao, L. Xu, Y. Ding, B. Niu, P. Xie, Z. 2234-2239. Bian, D. Zhang and Aihua Zhou, Eur. J. Org. Chem., 101.C. Zheng, X. Liu and C. Ma, J. Org. Chem., 2017, 82, 2016, 325-330; (c) M. Adib, S. R. Daryasarei, R. 6940-6945. Pashazadeh, M. Tajik and P. Mirzaei., Tetrahedron 102.H. Zhang, Y. Su, K. H. Wang, D. Huang, J. Lia and Y. Hu, Lett., 2016, 57, 3701-3705. Org. Biomol. Chem., 2017, 15, 5337-5344. Manuscript 88. M. K. Manna, G. Bairy and R. Jana, Org. Biomol. 103.P. Kumar, M. Gupta, V. Bahadur, V. S. Parmar and B. Chem., 2017, 15, 5899-5903. K. Singh Eur. J. Org. Chem., 2018, 1552-1558. 89. S. Maiti, L. Burgula, G. Chakraborti and J. Dash, Eur. J. 104.M. S. Segundo and A. Correa, Chem. Sci., 2019, 10, Org. Chem., 2017, 332–340. 8872-8879. 90. S. Paul, M. Bhakat and J. Guin, Chem. Asian J., 2019, 14, 3154-3160. 91. Carlos Santiago, Ibon Rubio, Nuria Sotomayor and

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