Metal-Catalyzed Oxidative Coupling of Ketones and Ketone Enolates

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2018, 50, 2150–2162 short review 2150 en

Syn thesis S. Murarka, A. P. Antonchick Short Review

a Sandip Murarka* 1,4-Dicarbonyl Andrey P. Antonchick*b,c O O R R a Department of Chemistry, Indian Institute of Technology Jodhpur, R R NH-65, Nagaur Road, Karwar-342037, Jodhpur District, Rajasthan, India [email protected] b Abteilung für Chemische Biologie, Max-Planck-Institut für Molekulare O Physiologie, Otto-Hahn-Straße 11, 44227 Dortmund, Germany R [email protected] c Fakultät Chemie und Chemische Biologie, Technische Universität Dort- COR R mund, Otto-Hahn-Straße 4a, 44227 Dortmund, Germany X ROH2C COR Cyclopropanes Heterocycles

Received: 25.02.2018 Accepted after revision: 21.03.2018 Published online: 03.05.2018 DOI: 10.1055/s-0037-1609715; Art ID: ss-2018-z0113-sr

Abstract Recent years have witnessed a significant advancement in the field of radical oxidative coupling of ketones towards the synthesis of highly useful synthetic building blocks, such as 1,4-dicarbonyl compounds, and biologically important heterocyclic and carbocyclic compounds. Besides oxidative homo- and cross-coupling of enolates, other powerful methods involving direct C(sp3)–H functionalizations of ketones have emerged towards the synthesis of 1,4-dicarbonyl compounds. Moreover, direct α-C–H functionalization of ketones has also allowed an efficient access to carbocycles and heterocycles. This review Sandip Murarka received his Ph.D. from WWU Münster, Germany un- summarizes all these developments made since 2008 in the field of der the supervision of Prof. Armido Studer. Subsequently, he worked as metal-catalyzed/promoted radical-mediated functionalization of ketones a postdoctoral research fellow in the laboratory of Prof. Herbert Wald- at the α-position. mann at Max Planck Institute Dortmund. Since May 2017, he has held 1 Introduction the position of an Assistant Professor at Indian Institute of Technology 2 Synthesis of 1,4-Dicarbonyl Compounds Jodhpur, India. His current research activities revolve around the study 3 Synthesis of Heterocyclic Scaffolds of novel activation modes and the development of transition-metal- 4 Synthesis of Carbocyclic Scaffolds free and transition-metal-catalyzed chemoselective and sustainable 5 Conclusion transformations. Andrey P. Antonchick received his Ph.D. from the Institute of Bioor- Key words ketone, oxidative coupling, C–H functionalization, cross- ganic Chemistry of the National Academy of Sciences of Belarus (Minsk, dehydrogenative coupling, radical Belarus) and the Max Planck Institute for Chemical Ecology (Jena, Ger- many) under the guidance of Prof. V. A. Khripach and Dr. B. Schneider.

After a postdoctoral appointment with Prof. M. Rueping at Frankfurt This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1 Introduction University, he joined the group of Prof. H. Waldmann. He was appoint- ed group leader at the Max Planck Institute of Molecular Physiology and An enolizable ketone typically reacts with a range of TU Dortmund. His research interests lie in the development of new reaction methodologies. electrophiles through the enol form to furnish conventional nucleophile–electrophile coupling products and this, thereby, ultimately leads to the α-functionalization of the ketone reported in 1935, when Ivanoff and Spasoff showed that the moiety.1 An alternative way to perform the α-functionaliza- enolate of phenylacetic acid undergoes oxidative homocou- tion of ketones would be through the oxidative coupling of pling in the presence of molecular oxygen or molecular io- the enolate thus providing a direct and convergent method dine.3 This exciting transformation turned out to be less to synthetically useful 1,4-dicarbonyl motifs (Scheme 1, synthetically useful due to low yields and multiple unwant- Path A).1,2 One advantage of such an oxidative coupling ed side products. This field remained unexplored until the strategy is that it obviates the need for functional group 1970s, when the interest towards the development of pre- umpolung and thereby streamlines the synthetic sequence. paratively and synthetically useful oxidative enolate cou- The first example of such an oxidative enolate coupling was pling was reinvigorated. In 1971, Rathke and Lindert docu-

Syn thesis S. Murarka, A. P. Antonchick Short Review mented a Cu(II)-promoted coupling of ester enolates to- the synthesis of 1,4-dicarbonyl compounds and diverse het- wards the synthesis of succinate esters.4 The first oxidative erocycles and carbocycles. This review specifically covers enolate coupling involving ketones dates back to 1975; the advancements made since 2008 in the field of the met- when Saegusa and co-workers documented the use of CuCl2 al-catalyzed couplings of ketones which occur through rad- as an effective oxidant for the dimerization of ketone eno- ical pathway and lead to the α-functionalization of ketones. lates.5 Subsequent years witnessed the usage of various This review does not cover oxidative coupling involving car- other oxidants6 and non-enolate carbonyl derivatives in ox- bonyls other than ketones (such as esters and amides) and idative coupling chemistry.2a In several of these cases more metal-free couplings involving ketones. challenging oxidative cross-coupling could be achieved, but typically they required stoichiometric advantage of one coupling partner. Recent years have witnessed significant 2 Synthesis of 1,4-Dicarbonyl Compounds advances in these areas in terms of efficient methodology development, cross-coupling with equal stoichiometry of Oxidative coupling of enolates through single-electron reacting partners, and attainment of high levels of diaste- oxidation represents a direct and straightforward approach reocontrol.2b Strategically, cross-dehydrogenative coupling for the construction of 1,4-diketones. Oxidative dimeriza- (CDC) between two simple C–H bonds leading to the formation of ketone-derived lithium enolates was first studied by tion of a C–C bond is of great interest due to its atom and Saegusa and co-workers in the 1970s.5,9 Formally, this step economy.7 In 1948, in one of the earliest examples of transformation utilizes the direct coupling of two identical CDC, Kharasch and co-workers showed that upon treatment sp3-hybridized carbon atoms with no substrate pre-func- with diacetyl peroxide, aliphatic ketones undergo dimeriza- tionalization. A comprehensive list of an analogous process tion through direct C–H functionalization to give the corre- using two different types of enolates allowing selective and sponding 1,4-dicarbonyl compounds.8 Interestingly, since controlled heterocoupling is quite brief. The first intermo- this initial report, noteworthy development has been made lecular oxidative cross-coupling was reported by Saegusa and powerful methods have emerged regarding the appli- and co-workers using at least a threefold excess of one of cation of CDC approach towards the synthesis of 1,4-dicar- the ketone coupling partners and gave the desired products in bonyl compounds through direct C(sp3)–H functionaliza- synthetically useful yields (Scheme 2).5 Although the power of tions of ketones (Scheme 1, Path B). this approach towards the synthesis of unsymmetrical 1,4- Importantly, 1,4-dicarbonyl compounds synthesized diketones is unquestionable, the necessity of using one cou- through these powerful oxidative coupling methods serve pling partner in manifold excess has restricted its use in more as highly useful synthetic precursors for various carbocyclic complex settings. and heterocyclic compounds (Scheme 1, Path C). Moreover, Saegusa, 1975 in recent years, several other direct oxidative homocou- O O O LDA, then Me plings of ketones and also cross-couplings between ketones + R R Me Me Me CuCl2 and diverse other coupling partners have been developed O (3 equiv) that lead to the formation of carbocycles and biologically Baran, 2006 O O O R4 important heterocycles. These cross-couplings may LDA, then R1 1 5 + 5 R R (Scheme 1, Path C) or may not (Scheme 1, Path D) go N R CuII or FeIII N through the intermediacy of a 1,4-dicarbonyl motif. R2 R3 R4 R2 R3 O (1-2 equiv) Flowers II, 2011 O O OM O enolate formation Path A LiHMDS t-Bu R1 + oxidative coupling Me t-Bu CTAN This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2 of enol derivatives O R (1 equiv) CTAN = Ceric tetra-n-butylammonium nitrate O O R4 Path B R3 1 1 Scheme 2 Oxidative cross-coupling of lithium enolates R direct C(sp3)-H functionalization R R2 R2 O Selective cross-coupling received no further attention and the field remained unexplored until 2006 when Baran Path D Carbocycles and Path C homo- and cross-coupling Heterocycles Paal–Knorr and co-workers reported the intermolecular oxidative het- diverse coupling partner Synthesis erocoupling of enolates.10 They showed that a selective het- Scheme 1 Radical couplings of ketones erocoupling between two different enolates can be achieved by exploiting the natural electronic or steric dif- ferences in both coupling partners. Accordingly, for the first The purpose of this brief review is to summarize all time a cross-coupling between a ketone and an amide with these recent contributions and to provide examples of oxi- equal stoichiometry of the reacting partners was demon- dative coupling involving α-functionalization of ketones for strated by Baran and DeMartino taking advantage of the

Syn thesis S. Murarka, A. P. Antonchick Short Review difference in oxidation potential of ketone and amide lithi- for the oxidative cross-coupling of tetralone derivatives to um enolates (Scheme 2).10a A subsequent report in 2008 de- afford unsymmetrical 1,4-diketones.15 Treatment of 2- tailing the full scope of the reaction revealed that good methyl-1-tetralone (4) with LDA followed by addition of yields were obtained across a range of substrates when ap- chlorosilane 5 resulted in the clean formation of the desired propriate lithium enolates were cross-coupled in the pres- unsymmetrical silyl bis-enol ethers 6, which were then ence of Fe(III)- or Cu(II)-based oxidants.10b Furthermore, it subjected to oxidative coupling conditions in the presence was also shown that best results were obtained in THF sol- of CAN to afford the desired diketones 7 with simultaneous vent. While these studies by Baran and co-workers provid- generation of a quaternary stereocenter (Scheme 3). Several ed important and much needed insight into oxidative het- methyl ketone derivatives 5 reacted with the tetralone erocoupling of lithium enolates, subsequent work by Casey component 4 to furnish the final products in moderate to and Flowers, supported by spectroscopic and mechanistic good yields. data, showcased that selective formation of cross-coupled products for the ketones they investigated was due to the Me Me R O Si O 11 LDA, then CAN Me heteroaggregation of the corresponding lithium enolates. Me O O R Me In an interesting finding, Daugulis and co-workers showed Me Me R NaHCO3 Si O that oxidative dimerization of ketone enolates can be car- Cl O 7 ried out using a copper catalyst and molecular oxygen as 456 O O O Ph 12 Me Me Me the terminal oxidant. The lithium enolates of diverse ke- t-Bu Ph tones underwent facile dimerization in the presence of O O O Cu(acac) catalyst, zinc chloride additive, and molecular ox- 2 41% 75% 54% ygen to afford the desired symmetrical 1,4-diketones in moderate to good yields. This is a significant improvement, Scheme 3 Oxidative coupling of 2-methyl-1-tetralone-derived unsymmetrical silyl bis-enol ethers as the existing oxidative homocouplings required metal oxidant in stoichiometric amounts. In 2011, Thomson and co-workers developed a method Following this in 2008, Thomson and co-workers inves- for the synthesis of axially chiral biphenols through the oxi- tigated the scope of the diastereoselective synthesis of dative enolate dimerization of enantioenriched monoketal linked complex bicyclic structures through the oxidative cyclohex-2-ene-1,4-diones.13 To this end, treatment of coupling of unsymmetrical silyl bis-enol ethers.16 Through enone precursors 1 with LDA, followed by oxidative cou- an extensive screening using several silyl bis-enol ethers pling catalyzed by CuCl2 furnished the dione product 2 while with varying silicon substituents, it was established that forging the hindered central σ-bond linkage. Finally, a Lewis sterically congested diisopropylsilyl bis-enol ether 8 was acid promoted loss of methanol with a concomitant double the optimal substrate giving the highest levels of yield and aromatization event furnished a range of desired biphenols 3 diastereoselectivity. The robustness of the protocol was with traceless central-to-axial chirality exchange (Table 1). demonstrated through the preparation of several linked bicyclic diketones 9 with high diastereoselectivity (Scheme 4). Table 1 Synthesis of Biphenols from 1,4-Diketones by Traceless Central- i-Pr i-Pr CAN (2.2 equiv) to-Axial Chirality Exchange Si O NaHCO3 (4.4 equiv) 2 O O DMSO (2 equiv) H R 1 2 O R R 1 O O OH MeCN/EtCN (6:1) R H LDA, then H Ar OMe –10 °C O OMe BF •OEt CuCl2 3 2 89 H OMe THF Ar toluene O Ar This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Ar 110 °C HO O O H MeO Ar Me MeO OMe MeO OMe H H 1 23 H H H O O O Ar Yield (%) of 2 (er) Yield (%) of 3 (er) Me 67% (d.r. 14:1) 82% (d.r. 20:1) 68% (d.r. 15:1) 4-MeOC6H4 50 (99:1) 86 (99:1) Scheme 4 Diastereoselective oxidative coupling of unsymmetrical silyl

4-FC6H4 66 (99:1) 88 (99:1) bis-enol ethers 2-naphthyl 51 (99:1) 82 (99:1) Taking this a step further in 2018, Thomson and Robin- In 1998, Schmittel and co-workers revealed that sym- son developed a modular approach based on the stereose- metrical and nonsymmetrical bis-enol ethers in the pres- lective coupling of symmetrical or unsymmetrical silyl bis- ence of ceric ammonium nitrate (CAN) undergo intramolec- enol ethers, followed by a ring-closing metathesis sequence ular oxidative coupling to generate 1,4-diketones.14 In order towards the synthesis of stereochemically rich polycyclic to further expand the scope of these initial findings, in 2007 compounds that are embedded in numerous bioactive nat- Thomson and co-workers documented a general strategy ural product families.17 To this end, optically active silyl bis-

Syn thesis S. Murarka, A. P. Antonchick Short Review

enol ether derivatives 10 bearing a vinyl or allyl group at Me Me R O Si CAN the 5-position were subjected to their previously docu- O MeMgBr, CuI; O O O Et3N dtbpy 2 1 2 R R R2 mented CAN-promoted oxidative coupling conditions to af- R R Me Me R Si ford diketo adducts 11, which upon ring-closing metathesis Me R1 Me Cl O R1 using Grubbs II catalyst delivered a range of polycyclic com- 13 51415 pounds 12 in moderate yield and good diastereoselectivity Me O Ph O Ph O O O O O (Scheme 5). Interestingly, several prepared compounds ex- O O Me Me hibited potent cytotoxic activity against a panel of tumor Ph Me Me Me cell lines. Importantly, enones were employed as starting 4 Me 4 Et Me 4 Me materials for the regioselective formation of the silyl bis- 47%, d.r. 2:1 57%, d.r. 1:1 58%, d.r. 1.6:1 54%, d.r. 1.7:1 enol ethers and also to ensure that subsequent oxidative Scheme 6 Merged conjugate addition/oxidative coupling towards 1,4- coupling takes place in the desired fashion. In addition, us- diketones ing an enantiomerically pure starting material was indis- pensable to this powerful reaction sequence, as the union of racemic precursors gave the undesired formation of diaste- cal to attaining high stereoselectivity. Accordingly, high reomeric mixtures. It is important to mention that the selectivity (up to 94:6) was obtained when the oxidative CAN-promoted oxidative heterocoupling of enol silanes has coupling was carried out at –30 °C and in the presence of been successfully applied as a key step in the total synthesis VO(Oi-Pr)2Cl as the oxidant. of the natural product propindilactone G.18 R2 VO(Oi-Pr)2Cl O i-Pr i-Pr 2 O R 2 9-BBN-H (3 equiv) 1 Si R B R CAN O O R1 O O O O 1 2 O NaHCO3 Grubbs II R R MS 4 Å, CDCl3 –30 °C, 19 h R1 R2 H H H O r.t., N2 1 2 R2 MeCN, EtCN R R R1 H CH2Cl2 1 13 16 17 DMSO R H Ph O Me O O Me H 10 11 12 Ph 4-F-C6H4 Ph 4-F-C6H4 Me Me O O Me O O Me O O O O O Ph H H O H H O 97% 95% 92% H H Me H H dl/meso = 77:23 dl/meso = 76:24 dl/meso = 91:9 Me Me H H H H Scheme 7 Oxovanadium(V)-induced oxidative homocoupling of boron

H H H enolates H Me 43% (d.r. 3:1) 57% (d.r. 20:1) 45% (d.r. 7:1) 44% (d.r. 20:1) Scheme 5 Stereoselective oxidative coupling/ring-closing metathesis Subsequently in 2015, Hirao and co-workers reported a sequence towards polycyclic scaffolds oxovanadium(V)-induced selective oxidative cross-coupling between boron 18 and ketone-derived silyl enolates 19 as In 2009, Thomson and Clift demonstrated a three-com- an efficient and straightforward strategy for the synthesis ponent, two-step merged conjugate addition/oxidative cou- of unsymmetrical 1,4-dicarbonyl compounds 20 (Scheme pling strategy using CAN and 2,6-di-tert-butylpyridine 8).21 The reactivity difference between boron and silicon in (dtbpy) towards the synthesis of a diverse collection of 1,4- the enolates 18 and 19 proved to be crucial as it allowed se- diketones 15 in moderate yields (Scheme 6).19 The desired lective one-electron oxidation of the more reactive boron unsymmetrical silyl bis-enol ethers 14 required for the oxi- enolate 18 leaving the silyl enolate 19 intact. Strategically,

dative coupling were formed in the first step by 1,4-addi- selective one-electron oxidation of the boron enolate 18 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tion of methylmagnesium bromide with subsequent trapping generates an electrophilic α-radical species, which is imme- of the thus-generated enolate by chlorosilyl enol ether 5. diately trapped by the silyl enolate 19. A broad substrate In 2014, Hirao and co-workers developed an oxidative scope with regard to both enolates was demonstrated and homocoupling of boron enolates 16 using oxovanadium(V) the resulting 1,4-dicarbonyls 20 were obtained in good compounds to give the corresponding 2,3-disubstituted yields. In 2017, they also showed that the same oxovanadi- 1,4-diketones 17 in good yields (Scheme 7).20 The required um(V)-induced cross-coupling strategy can be extrapolated boron enolates 16 were prepared via the 1,4-hydroboration to the cross-coupling of various combinations of boron and of enones 13; the geometric configuration of the resulting silyl enolates in a ketone–ester, ester–ester, amide–ester, enolate 16 was established using 1H NMR spectroscopy. In- and amide–ketone enolate coupling.22 These findings un- terestingly, the choice of oxovanadium(V) oxidant was criti- equivocally established the versatility of this oxovanadium(V)-induced oxidative cross-coupling strategy.

Syn thesis S. Murarka, A. P. Antonchick Short Review

O Ar2 O O AgF (10 mol%) 5 6 2 OSiMe3 VO(OEt)Cl2 O R R R 1 + 2 1 B 5 (1.25 equiv) 4 Ar Ar R O R R R1 R2 xylene, air, 140 °C, 4–10 h + R4 R1 1 23 24 25 Ar O R2 CH Cl , N 2 3 1 R6 2 2 2 R R O R r.t. 18R3 19 20 Me O O O O NO2 F t-Bu OEt Ph Ph Ph Ph Bn O Me O Bn O Me Me O O O O O 71% 63% 85% (d.r. 56:44) 85% Ph Ph Ph n-Bu Ph Ph n-Bu Scheme 8 Oxovanadium(V)-induced oxidative heterocoupling of enolates Ph O O O O

In 2015, Wang and co-workers developed an efficient Me F Cu(II)-promoted direct oxidative coupling between two Cl 68% (d.r. 1.2:1) 71% (d.r. 1.3:1) 93% (d.r. 1.4:1) 89% (d.r. 1.4:1) C(sp3)–H bonds in the α-position to a carbonyl group as a more attractive way to build the 2,3-disubstituted 1,4-di- Scheme 10 Ag(I)-catalyzed oxidative coupling of two C(sp3)–H bonds ketone motif 22 (Scheme 9).23 The method features a broad adjacent to a carbonyl group substrate scope and high functional group tolerance. Mech- anistically, it was proposed to proceed through the inter- Under the catalysis of pyrrolidine and Cu(ClO4)2·6H2O and mediacy of radicals. in the presence of MnO2 and air, several dicarbonyl compounds were obtained. According to the proposed mecha- O Ar O Cu(OAc)2•H2O (1 equiv) nism (Scheme 11), pyrrolidine initially reacts with cyclo- R Ar R hexanone (27a) (a representative carbonyl) to form enamine R xylene, 140 °C Ar O 21 22 A, which then undergoes single-electron oxidation by Cu(II) Br OMe to generate the corresponding radical cationic enamine B. Then B reacts with styrene (26a) to form radical intermediate C, which upon reaction with oxygen and concomitant O O O Br O hydrolysis delivers peroxide intermediate D. Finally, inter- Ph Ph Me n-Bu Ph Ph Me n-Bu mediate D under copper catalysis affords 1,4-diketo species O O Br O O 28.

OMe Cat. (30 mol%) Br Cu(ClO4)2•6H2O O 2 80% (d.r. 6.2:1) 90% (d.r. 1.9:1) 86% (d.r. 1.2:1) 91% (d.r. 1.4:1) (50 mol%) O R MnO (2 equiv) 1 1 2 R Ar + R Ar N Cl 3 H2 Scheme 9 Cu(II)-promoted oxidative coupling of two C(sp )–H bonds 2 DMF/H O, air R 2 O 70 °C Cat. adjacent to the carbonyl group 26 27 28

O O O O Me Contemporaneously, they developed a more sustainable Ph Ph Ph O O O silver-catalyzed protocol to achieve a similar cross-de- O MeO 55%61% 64% 43% hydrogenative coupling of two C(sp3)–H bonds for the syn- OH 24 O [Cu] O thesis of 1,4-diketones with air as the terminal oxidant. O O2 Ph

Ph This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. This catalytic CDC protocol is highly attractive, as besides 27a D 28a O O H2O homocoupling it also allows the cross-coupling of two dif- O N 2 H ferent ketones 23 and 24 under similar conditions to afford H2O the corresponding products 25 in good yields (Scheme 10). N In their pioneering studies in 2007, MacMillan and co- Ph N workers exploited their novel organocatalytic singly occu- A pied molecular orbital (SOMO) activation strategy to report C II N Cu the first asymmetric aldehyde α-enolation leading to the I Ph Cu MnO formation of γ-ketoaldehydes starting from simple alde- 26a B 2 hydes and enolsilanes.25 In 2010, Huang and Xie developed a merging organocatalyst and transition-metal-catalyzed Scheme 11 The cascade carbo-carbonylation of styrenes and ketones carbo-carbonylation of styrenes 26 with ketones 27 by cascade SOMO catalysis and oxidation to furnish 1,4-dicarbon- Along these lines, Koike, Akita, and Yasu developed a yl compounds 28 in moderate to good yields (Scheme 11).26 visible-photoredox-catalyzed oxidative cross-coupling of enamines and silyl enol ethers in the presence of quinone

Syn thesis S. Murarka, A. P. Antonchick Short Review

oxidant to furnish the corresponding γ-diketones in moder- Cu(OAc)2•H2O (20 mol%) R O R ate yields.27 In a conceptually novel approach, Xing and co- O Ag2O (10 mol%) Ar R O2 (1 atm), TFA (1.6 equiv) workers documented a copper/manganese-cocatalyzed and xylene, 140 °C Ar Ar tert-butyl hydroperoxide (TBHP) promoted direct oxidative 21 29 coupling of styrene derivatives 26 with ketones 27 through O O MeO OMe Me Me n-Bu n-Bu O 3 C(sp )–H bond functionalization to afford 1,4-dicarbonyls Br Br 28.28 Various ketones underwent a smooth free-radical addition to styrenes to furnish a range of 1,4-diketone compounds with excellent regioselectivity (Scheme 12). Simi- 70% 77% 64% larly, Christoffers and Geibel reported a cerium-catalyzed cou- Ag2O/O2 O pling of oxo esters with enol acetates for the synthesis of 1,4- Cu(II) Cu(I) O O O Ar TFA R R 29 R diketones using atmospheric oxygen as the oxidizing agent. Ar Ar R (SET) R R Paal–Knorr Ar AcOH reaction Ar Ar 21 A 22 29 Cu(OTf)2 (5 mol%) O MnCl2•4H2O (5 mol%) O DBU (1.5 equiv) O R2 Scheme 13 Cu/Ag-catalyzed oxidative coupling of ketones for the TBHP (4 equiv) 1 1 R synthesis of tetrasubstituted furans Ar + R Ar 2 60 °C, neat R O 26 27 28 O O O O Me one-pot fashion under different conditions to furnish tetra- Me Et substituted furans (Conditions A), thiophenes (Conditions Ph Ph Ph O O O MeO O B), and pyrroles (Conditions C) in good yields (Scheme 14). 57%50% 50% 55%

Scheme 12 Cu/Mn-cocatalyzed oxidative coupling of ketones and styrenes 1. AgF (10 mol%), air, xylene X O 140 °C, 4–10 h R R Ar R 2. Conditions A/B/C Ar Ar 21 30 3 Synthesis of Heterocyclic Scaffolds X = O, S, NH X = O, Conditions A: TsOH (1.5 equiv), 3 h

O O Me O n-Bu The direct oxidative C–H functionalization of ketones Me n-Bu Br Br has been successfully applied in the synthesis of several heterocycles, such as furans, dihydrofurans, thiophenes, Br Br and pyrroles, that are valuable five-membered heterocycles 82% 85% MeO 72% OMe embedded in multiple natural products, pharmaceuticals X = S, Conditions B: Lawesson's reagent (1.5 equiv), toluene, reflux, 3 h and materials.30 In 2015, Wang and co-workers developed a S S S copper and silver cocatalyzed coupling of C(sp3)–H bonds that are adjacent to a carbonyl group to provide a direct and efficient route to a diverse collection of tetrasubstituted Br Br furan derivatives 29 using molecular oxygen as the terminal 71% 70% MeO 74% OMe 23 oxidant (Scheme 13). Importantly, the oxidative coupling X = NH, Conditions C: AcONH4, 120 °C, 8 h did not occur when carried out in the presence of the radi- H H H N cal inhibitor TEMPO. Based on this radical trapping experi- N N ment, they proposed that the reaction begins by deprotona-

tion and single-electron-transfer oxidation of ketone 21 by This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the Cu(II) catalyst to form alkyl radical A and Cu(I). Then Me 86% Me F 90% F O2N 91% NO2 the resulting alkyl radical A undergoes homodimerization Scheme 14 Ag-catalyzed one-pot synthesis of furans, thiophenes, and to give 1,4-dicarbonyl 22, which finally, under acidic condi- pyrroles tions, produces tetrasubstituted furans 29. Cu(I) is oxidized by the Ag2O/O2 system to regenerate Cu(II) and complete the catalytic cycle. Furans have also been synthesized through intermolec- In a subsequent report,24 they demonstrated a silver- ular oxidative coupling between ketones and electron-defi- catalyzed general oxidative coupling approach for the syn- cient alkenes. To this end, in 2013 Zhang and co-workers re- thesis of polysubstituted furans, thiophenes, and pyrroles ported a novel copper-mediated intermolecular annulation (Scheme 14, see also Scheme 10). Initially, silver-catalyzed of alkyl ketones 31 with acrylic acids 32 for the synthesis of oxidative coupling of two C(sp3)–H bonds generates 1,4- 2,3,5-trisubstituted furans 33 (Scheme 15).31 It is important diketones, which subsequently undergo cyclization in a to mention that the reaction was more effective in the pres-

ence of both copper salts [CuCl and Cu(OAc)2·H2O] and yields decreased in the absence of either of the copper

Syn thesis S. Murarka, A. P. Antonchick Short Review

sources. The reaction between ketone 31a and cinnamic O Cu(OAc)2•H2O (20 mol%) R2 H2O (3 equiv) + CO2H acid (32a) was completely suppressed when carried out in R1 R3 DMA, 120 °C, 7 h 1 3 the presence of TEMPO as a radical inhibitor, which sup- R2 R O R 31 32 33 ports the intermediacy of radicals in this reaction. Accord- Me Me Br Et ing to the proposed reaction mechanism, in the first step, Ph upon reaction with copper salts, the cinnamic acid 32 gen- O Ph O Ph Ph O Ph O O erates Cu(II) cinnamate A and the alkyl ketone 31 produces 56% 54% 64% 40% the corresponding alkyl radical B (Scheme 15). Addition of Control Experiment Cu(OAc) ·H O (20 mol%) Me O 2 2 the generated alkyl radical B to the α-position of the double H O (3 equiv) CO2H 2 Me +Ph bond in Cu(II) cinnamate A, followed by single-electron- Ph BHT or quinone (1.5 equiv) Ph O Ph transfer oxidation delivers the carbocationic intermediate DMA, 120 °C, air, 9 h 31a 32a 33a (52% yield) D. Subsequently, D undergoes intramolecular cyclization to give intermediate E, which upon deprotonation and elimi- Scheme 16 Cu-catalyzed synthesis of furans using Cu(OAc)2·H2O nation delivers the corresponding furan product 33. Also in 2015, Hajra and co-workers demonstrated a cop- O CuCl (1 equiv) R2 Cu(OAc) •H O (1equiv) per-mediated annulation of alkyl ketones 31 and β-nitro- + CO2H 2 2 R1 R3 styrenes 34 for the synthesis of 2,3,5-trisubstituted furans DMF, air, 140 °C 1 3 R2 R O R 31 32 33 35 using tert-butyl hydroperoxide as an oxidant (Scheme 33 Me Me Me Me Ph 17). In contrast to their previous report, they showed, based on radical trapping experiments, that this reaction Ph Ph O Ph O O Ph O Ph proceeds through a radical pathway. S S 53% 55% 57% 43%

Control Experiment O CuBr·SMe2 (1 equiv) 2 CuCl (1 equiv) Me TBHP (1 equiv) R O Cu(OAc) •H O (1equiv) + NO2 CO2H 2 2 R1 Ar Me + Ph DMF, 120 °C, air 1 Ph 2 R Ar TEMPO (2 equiv) Ph O Ph R O 31a 32a DMF, air, 140 °C 33a 31 34 35 <5% GC yield Me Bn Plausible Mechanism

Cu(II) Ph Me O CO2H CO2Cu(II) O O R3 R3 SMe Me Me A 32 55% 52% 48% O O O CO Cu(II) SET 2 R3 1 1 1 Scheme 17 Cu-mediated annulation of ketones and β-nitrostyrenes R [O] R R C R2 R2 R2 for the synthesis of substituted furans B 31 SET [O]

2 R2 R CO2Cu(II) O CO2Cu(II) deprotonation R3 Antonchick and Manna showed that besides activated R1 3 1 R3 elimination R1 R R O O R2 alkenes, electron-deficient alkynes can also be employed in 33 E D this type of oxidative cross-coupling reaction. Accordingly,

Scheme 15 Cu-promoted synthesis of furans using CuCl and Cu(OAc)2·H2O they developed a copper-catalyzed oxidative coupling, using di-tert-butyl peroxide (DTBP), between acetophenones 36 and electron-deficient alkynes 37 for the synthesis of Following this report, in 2015 Hajra and co-workers re- trisubstituted furans 38 (Scheme 18).34 Subsequent to this

ported a similar decarboxylative annulation between ke- report, Luo, He, and co-workers demonstrated a similar This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tones 31 and acrylic acids 32 towards the regioselective Cu(I)-catalyzed oxidative annulation between substituted synthesis of trisubstituted furans 33.32 The method was acetophenones 39 and alkynoates 40 using benzoyl perox- shown to be quite robust and a library of furan derivatives ide (BPO) as an external oxidant (Scheme 18).35 Both proto- was prepared. Interestingly, whereas the method of Zhang cols are mechanistically similar and work quite efficiently and co-workers required two different copper salts in stoi- giving multisubstituted furans in good yields. In contrast to chiometric amounts, the protocol of Hajra and co-workers the protocol of Antonchick and Manna, which exclusively utilized a single copper salt in catalytic amounts and a stoi- worked for electron-poor acetophenones 36, the method of chiometric amount of water as an important additive. Fur- Luo, He, and co-workers was shown to be applicable to elec- thermore, Hajra and co-workers ruled out the possibility of tron-rich acetophenones 39 as well. a radical pathway, as radical scavengers like quinone and 2,6-di-tert-butyl-4-methylphenol (BHT) did not inhibit the reaction between 31a and 32a and the corresponding furan 33a was obtained in 52% yield (Scheme 16).

Syn thesis S. Murarka, A. P. Antonchick Short Review

Antonchick's work I II 2 [Cu ] + (t-BuO)2 2 t-BuO-[Cu ] CuBr•SMe (20 mol%) CO R2 CO2Et CO R2 2 2 O 2 bipy (30 mol%) DTBP (3 equiv) t-BuO-[CuII] O + 37a CH3 CO R2 I R1 O 2 [Cu ] DCE, 75 °C, Ar, 5-8 h O OH O O OEt 2 CO2Et CO2R R1 OEt 36 37 38 Ar Ar t-BuOH Ar Ar B CO2Et 36 A O CO Et CO Et t-BuO-[CuII] 2 2 t-BuO-[CuII]

O CO2Et CO Et CO Et O O O 2 O 2 [CuI] t-BuO Br S CuIII 70% NC 72% 48% O OEt t-BuO O OEt OEt OEt He's work Ar Ar R2 CO R3 CO R3 2 O 2 CuI (20 mol%) H O C O BPO (2 equiv) F + CO R3 R1 O 2 2 MeCN, 100 °C,10 h O O R 3 t-BuO CO2R CO Et III III R1 2 Cu Cu 39 40 41 O OEt OH OEt CO2Me OEt OEt Ar CO Et CO2Me O 2 I Ar Ar Ph CO2Me [Cu ] t-BuOH 38a E O D O O CO2Me CO2Me O Ph CO2Me MeO O Scheme 19 Proposed mechanism for the Cu-catalyzed annulation of 92% 83% 81% O2N acetophenones and alkynoates Scheme 18 Cu-catalyzed annulation of acetophenones and alkynoates for the synthesis of substituted furans workers and based on their experiments and density functional calculations they unambiguously established that the According to the proposed mechanism,34 first the Cu(I) reaction is indeed going through a radical intermediate.37 species is oxidized to Cu(II) in the presence of DTBP The reaction between phenylacetylene (42a) and ethyl aceto- (Scheme 19). The enol form of the acetophenone derivative acetate (43a) carried out under the optimized conditions is then oxidized to the corresponding alkyl radical A by the was completely inhibited upon addition of TEMPO or BHT Cu(II) species. Subsequently, radical A undergoes addition as radical scavengers (Scheme 20). to the electron-deficient alkyne 37a to give intermediate B, which after oxidative addition of Cu(II) generates interme- Lei's work Ag CO (2 equiv) COR2 O O 2 3 diate C. Intermediate C is in equilibrium with intermediate KOAc (2 equiv) Ar + 1 2 D through keto–enol tautomerization. A ligand exchange in R R DMF, 80 °C, N , 12 h 1 2 Ar O R intermediate D forms metallocycle E, which finally under- 42 43 44 goes reductive elimination to afford product 38a. The Cu(II) CO2Et CO2Et CO2Et COPh catalyst is regenerated by oxidation of Cu(I) with DTBP. In Me O O Me an alternative pathway, radical B can be oxidized to the cor- Ph O Me Ph O Ph S responding cation F by Cu(II), which concomitantly under- 89% 76% 80% 65% goes intramolecular cyclization to the desired final product Novak and Stirling's mechanistic studies 38a. However, this pathway was considered to be less likely, Ag2CO3 (2 equiv) CO2Et O O KOAc (2 equiv) as in control experiments the authors were not able to trap Ph + Me OEt TEMPO (1 equiv) Ph O Me the cationic intermediate using various nucleophiles. 42a 43aDMF, 80 °C, N2, 12 h 44a 15% GC-MS conversion

In 2012, Lei and co-workers demonstrated that simple This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Ag2CO3 (2 equiv) CO2Et unactivated terminal alkynes 42 can also be employed in O O KOAc (2 equiv) Ph + direct oxidative cross-coupling by using 1,3-dicarbonyl Me OEt BHT (1 equiv) Ph O Me compounds 43 possessing an active methylene group in- 42a 43aDMF, 80 °C, N2, 12 h 44a 0% GC-MS conversion stead of simple alkyl ketones as the other coupling partner. They developed a silver-mediated CDC between 1,3-dicar- Scheme 20 Ag-promoted oxidative coupling of arylacetylenes with bonyl compounds 43 and arylacetylenes 42 furnishing a 1,3-dicarbonyls range of polysubstituted furans 44 in good yields (Scheme 20).36 The reaction worked only with terminal alkynes and Li and co-workers developed a manganese-mediated ef- trace product formation was observed in cases using inter- ficient synthesis of dihydrofurans 46 through direct oxida- nal alkynes. It was speculated that this transformation tive coupling of enamides 45 and 1,3-dicarbonyl com- might not proceed through an oxidative radical cyclization. pounds 43 (Scheme 21).38 Replacing 1,3-dicarbonyl com- In 2014, the mechanism of this silver-mediated oxidative pounds 43 with 2-substituted 1,3-dicarbonyl compounds in coupling reaction was studied by Novák, Stirling, and co- the reaction with enamides under otherwise unchanged conditions, delivered (Z)-dicarbonyl enamides. Importantly,

Syn thesis S. Murarka, A. P. Antonchick Short Review

dihydrofurans 46 were conveniently transformed into the In 2017, Yu and co-workers developed a Fe(OAc)2-cata- corresponding furans 44 and pyrroles 47 in good yields via lyzed cross-dehydrogenative coupling between 1,3-dicar- the classical Paal–Knorr reaction (Scheme 21). bonyl compounds 49 and α-oxoketene dithioacetals 48 using tert-butyl peroxybenzoate (TBPB) for the synthesis of a AcHN O NHAc O O Mn(OAc)3•2H2O (3 equiv) R1 library of tetrasubstituted furans 50 in good yields (Scheme KOAc (2 equiv) Ar + 39 Ar R1 R2 23). Importantly, the highly functionalized furan deriva- MeCN, Ar, 80 °C COR2 45 43 46 tives are amenable to further synthetic manipulation

AcHN O AcHN O O through palladium-catalyzed selective C–S bond cleavage Me Ph AcHN AcHN O Me Ph Ph Ph and concomitant arylation to yield 2-arylfurans 51 or CO t-Bu COPh S CO Et 2 O 2 through condensation with hydrazine to yield 2,3-furan- 65% 30% 80% 60% fused pyridazinones 52. R RNH2 (1.5 equiv) AcHN TsOH O O R1 Ar R1 Ar N R1 TsOH (1.1 equiv) (1.1 equiv) Ar O COR4 Fe(OAc)2 (2 mol%) 1 toluene, 100 °C toluene O O TBPB (3 equiv) R OC 2 COR2 1 47 2 46 COR 110 °C 44 R + 3 COR 3 4 R up to 99% yield up to 99% yield R R DMA, 120 °C, 20 h 2 2 2 O 10 examples 10 examples R S SR R S 48 49 50 O O CO Et Scheme 21 Mn-mediated oxidative coupling of enamides and 1,3-di- CO2Et CO2Et 2 carbonyl compounds S MeOC Me Me Me Br O MeS O MeS O EtS 61% 70% 74% Based on radical trapping experiments, a radical mecha- O O CO Et CO2Me CO2Et 2 nism was proposed for this transformation (Scheme 22). S MeOC

Ph CF3 The reaction begins with the oxidation of 1,3-dicarbonyl MeO O MeS O MeS O EtS compounds 43 by Mn(OAc)3 to generate an electron-defi- 67% 65% 80% cient radical A, which subsequently adds to the electron- ArB(OH)2 (2 equiv) H O Pd(PPh3)4 O N O rich enamide 45 to generate radical B. Radical B gets further CO2Et CO2Et N (7.5 mol%) NH2NH2•H2O 1 CuI (2 equiv) 1 (5 equiv) oxidized by Mn(OAc)3 into carbocation C or iminium ion C′, R 3 R R3 R1 R R3 which readily undergoes cyclization/deprotonation to af- O Cs2CO3 (2 equiv) O MeCN, reflux Ar dioxane, 80 °C MeS O ford desired dihydrofuran 46. Under the influence of acid 51 50a MeS 52 8 examples 4 examples 46 undergoes ring cleavage to give imine D or enamide D′, up to 93% yield up to 86% yield which further hydrolyzes to the corresponding 1,4-dicar- Scheme 23 Fe-catalyzed cross-dehydrogenative coupling of internal bonyl intermediate E. The intermediate E then delivers the alkenes and 1,3-dicarbonyl compounds corresponding furans 44 and pyrroles 47 under Paal–Knorr conditions. Lei and co-workers reported a copper-catalyzed oxidative coupling between styrenes and 1,3-dicarbonyl com- NHAc NHAc NHAc 2 pounds in the presence of di-tert-butyl peroxide as the ex- COR COR2 45 Mn(III) Ar Ar Ar ternal oxidant to provide highly substituted dihydro- 1 1 O O 40 O R O R R2OC R2OC furans. Moreover, they studied the Cu(I)/Cu(II) redox 43 A BCR1 R1 process involved in the oxidative cyclization of β-ketocar- bonyl derivatives by X-ray absorption and EPR spectroscopy H NHAc and provided evidence supporting the reduction of Cu(II) to AcHN O + AcHN AcHN R1 H O R1 O R1 Ar Ar Ar Ar Cu(I) by 1,3-diketones. In an interesting report, Maiti and This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. + – H O R2OC co-workers demonstrated a copper-mediated annulation of COR2 COR2 2 46 COR C' R1 aryl ketones 53 and styrenes 54 allowing efficient access to + – H a diverse range of dihydrofurans 55 in good synthetic yields Ar O R1 (Scheme 24).41 Meanwhile, along the same lines, Hajra and

1 1 1 Ac O R Ac O R H O+ O R 44 COR2 co-workers showed that aryl ketones 53 and styrenes 56 N NH 3 O H+ R can also be oxidatively cross-coupled in the presence of cat- 2 2 2 Ar COR Ar COR Ar COR Ar N R1 RNH DD'E2 alytic amounts of Cu(II) salts to furnish multisubstituted furans 57 (Scheme 24).42 Importantly, aliphatic ketones as 47 COR2 well as aliphatic alkenes are not viable substrates under Scheme 22 Mechanism of Mn-mediated oxidative coupling of enam- both Maiti and Hajra’s conditions. Both reactions go ides and 1,3-dicarbonyl compounds through the intermediacy of radicals as demonstrated by the use of radical scavenger experiments. Interestingly, as per the proposed mechanism of Hajra and co-workers, formation of furans 57 goes through the intermediacy of dihy-

Syn thesis S. Murarka, A. P. Antonchick Short Review

drofurans 55. Based on the proposed mechanism, dihydro- O O 2 furans 55a, following further oxidation under Hajra’s oxida- R n tive conditions, generate carbocationic intermediate 58, R2 61 R1 63 Cu(OAc) •H O Cu(OAc) •H O which finally undergoes 1,2-aryl shift and elimination to O 2 2 2 2 O R1 R2 (2 equiv) (1 equiv) n furnish desired furan derivative 57 (Scheme 24). Similarly R1 R2 P(t-Bu)3•HBF4 60 P(t-Bu)3•HBF4 in 2017, Lei and co-workers reported a facile CuCl2-cata- (10 mol%) (10 mol%) Ag2CO3 (3 equiv) Ag2CO3 (3 equiv) lyzed oxidative cyclization of aryl ketones and styrenes to- 64 TFE (3 mL) 1-Ad-COCl (20 mol%) 62 wards the synthesis of multisubstituted furan derivatives.43 DCE, 130 °C, 24 h DCE, 130 °C, 24 h Me F O Interestingly, through X-ray absorption and electron para- Ph O Ph O O Ph magnetic studies they revealed that DMSO, besides serving O as a solvent, plays the crucial role of an oxidant to promote O Ph Me the oxidation of Cu(I) to Cu(II). 65% 75% 62a, 58% 72%

Maiti's work 3 3 R R 1 O Cu(OAc)2•H2O (1 equiv) R 2 O O 1 + R O Ph R 67% 92% 52% Ar1 DCE, 110 °C, 24 h 2 R2 Ar2 Ar Cu O (1 equiv) Ar1 O 2 53 54 55 1-Ad-CO2H (1.5 equiv) up to 83% yield 2 34 examples R O Cu(OAc) •H O (2 equiv) 2 2 O Hajra's work Ag2CO3 (3 equiv) CuCl (20 mol%) 1 2 2 + R R R1 or R1 Ar2 O R2 t-BuOH, MS 4Å, 130 °C Cu(OTf)2 (20 mol%) R1 1 + Ar 2 Ar DMF, 120 °C, 16 h 1 2 63a65 (2 equiv) 66 Ar O R 53 56 57 Ph Ph Ph Ph up to 95% yield 27 examples O O O O Ph Me Et Ac 2 2 2 Ar Ar R1 Hajra's R1 1,2-Ar R1 R1 R2 conditions R2 shift R2 R2 Ar2 Ar2 + 72% 75% 67% 62% 1 O O – H Ar Ar1 Ar1 O Ar1 O 55a 58 59 57 Scheme 25 Regiospecific synthesis of fused furans and naphthofurans Scheme 24 Oxidative coupling of ketones and styrenes Afterwards, an oxidative cyclization results in dihydrofuran Also in 2017, Maiti and co-workers developed a general derivative F, which finally yields the desired product 64a and elegant oxidative [3+2] annulation between a variety of through a radical-based dehydrogenation/oxidation sequence. cyclic ketones 61 and 63 and diverse alkenes 60 using Cu(OAc) in combination with a tri-tert-butylphoshine li- 2 II Cu (OAc)2 gand to furnish a diverse collection of fused furans 62 and 0 L Ag +CO2+H2O O 44 II naphthofurans 64 under mild conditions (Scheme 25). LCu (OAc)2 OAc 63a Importantly, naturally occurring chiral substrates, such as Ag2CO3+AcOH O CuL OAc (R)-(–)-carvone underwent smooth reaction with styrene R1 to provide fused furan 62a in 58% yield. Using adamantane- A L 1 E O I 1-carbonyl chloride as an additive was essential to the syn- O R Cu I F Cu OAc rate-determining thesis of fused furans 62, but it proved to be ineffective in step AcOH SET R1 II kH/kD = 3.37 increasing the yield of naphthofurans 64. Moreover, the Cu This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. generality of the method was further demonstrate by react- L L II I Cu Cu OAc ing 1-tetralone (63a) with several internal alkynes 65 fur- O OAc O L nishing 2,3-disubstituted naphthofurans 66 in good yields I 1 D Cu OAc 64a O R B (Scheme 25). Use of molecular sieves as a drying agent and O tert-butyl alcohol as the solvent was critical in obtaining R1 SET 60 good yields in this transformation. C Based on several control experiments, a radical-based Scheme 26 Proposed mechanism for the synthesis of fused furans and mechanism was proposed as shown in Scheme 26. The re- naphthofurans action begins by the coordination of a copper complex with 1-tetralone (63a) to generate intermediate A, which upon elimination of acetic acid leads to B. Subsequently, single- In 2008, Chiba and Narasaka documented a Cu(II)-cata- electron transfer from B, followed by radical addition of C lyzed oxidative annulation between α-(alkoxycarbonyl)- onto the β-position of alkene 60 provides intermediate D. vinyl azides and ethyl acetoacetate towards the synthesis of 1H-pyrroles.45a However, the inevitable difficulties in intro-

Syn thesis S. Murarka, A. P. Antonchick Short Review ducing an alkoxycarbonyl moiety at the α-position of the formed into 74 through hydrolysis and subsequent diesteri- vinyl azide and the inability of 1,3-diketones other than fication and into 75 through reduction using lithium ethyl acetoacetate to participate in this copper-catalyzed aluminum hydride (Scheme 28). protocol, prompted the further development of a more gen- Ar O eral method. Accordingly, they developed a Mn(OAc)3-cata- O CuI (20 mol%) bipy (30 mol%) lyzed coupling between diverse vinyl azides 67 and a vari- O DTBP (5 equiv) N R + ety of 1,3-dicarbonyl compounds 68, including the corre- Ar Me PhCl, 110 °C O N O sponding diketone analogues, to afford a versatile collection O Ar, 16 h R of 1H-pyrroles 69 (Scheme 27).45b 72 (2 equiv) 36 73 MeO2C F MeO2C Chiba and Narasaka's work O NC 2 Mn(OAc)3•2H2O (10 mol%) COR O R1 O O AcOH (2 equiv) O F O + O O 2 MeOH, 40 °C 1 Me N3 Me R R N H 67 68 O O 69 N MeO2C O N O Me Ph Adimurthy's work Cl Cl R3 1 75% 72% 61% (10:1) 70% R O Cu(OAc) •H O (10 mol%) 2 2 Br + R3 2 1 R2 N3 R DMF, 40 °C R N H OH O O 67 70 71 1. HCl(aq) CO i-Pr LiAlH4 2

2. i-PrOH Scheme 27 Oxidative coupling of vinyl azides with 1,3-dicarbonyl Br p-TsOH CO2i-Pr compounds or ketones for the synthesis of pyrroles N O N O Me Me 75 73a 74 In 2015, Adimurthy and co-workers showed that simple Scheme 28 Cu-catalyzed annulation of electron-deficient alkenes ketones 70, instead of activated 1,3-dicarbonyl compounds, can also be employed in this kind of transformation. A copper-catalyzed direct C(sp3)–H functionalization of ketones Mechanistically, first Cu(I) is oxidized to a Cu(II) species 70 with vinyl azides 67 was developed for the straightfor- by DTBP (Scheme 29). In the following step, acetophenone ward and efficient synthesis of 2,3,5-trisubstituted 1H-pyr- 36 through its enol form A gets oxidized by the Cu(II) spe- roles 71 (Scheme 27).46 Several electronically and structur- cies to alkyl radical B. The resulting radical B then adds to ally diverse vinyl azides reacted with both aliphatic and ar- the maleimide derivative 72 to produce C, which is stabi- omatic ketones to furnish the desired products in moderate lized through the resonance form C′. Subsequent addition to good yields. of C on the Cu(II) species generates intermediate D, which upon enolization at the keto functionality and ligand exchange delivers E. Importantly, formation of E is the stereo- 4 Synthesis of Carbocyclic Scaffolds determining step of this annulation process. Finally, reductive elimination of Cu(I) from E generates the final product Strained carbocycles, such as cyclopropanes, impart 73 and the Cu(II) catalyst is regenerated by oxidation of unique reactivity in organic synthesis and are embedded in Cu(I) by DTBP. many natural products and medicinally important com- 47 pounds. Antonchick and Manna have developed a copper- I II This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 2 [Cu ] + (t-BuO)2 2 t-BuO-[Cu ] O catalyzed cross-dehydrogenative annulation of electron-de- O ficient alkenes 72 and acetophenones 36 involving direct O N R Ar double C–H functionalization at the α-position of the ke- C' O t-BuO-[CuII] N R I O tone using di-tert-butyl peroxide as the terminal oxidant [Cu ] 72 O towards the stereoselective synthesis of fused cyclopro- O OH O O N R panes 73 (Scheme 28).48 A broad substrate scope with re- Ar Ar t-BuOH Ar Ar 36 A B C O gard to electronically diverse acetophenones 36 and N-al- t-BuO-[CuII] kyl-substituted maleimides 72 gave versatile fused cyclo- t-BuO O O III O III Cu propane scaffolds 73 in good yields. Moreover, besides N- O Cu O O substituted maleimides, other electron-deficient alkenes, N R N R N R Ar Ar Ar such as acrylic acid derivatives, were shown to be tolerated I 73 O [Cu ] E O t-BuOH D O under the reaction conditions. Importantly, the highly functionalized final products were amenable to further synthet- Scheme 29 Proposed mechanism for the Cu-catalyzed cyclopropane ic transformations. Accordingly, product 73a was trans- synthesis

Syn thesis S. Murarka, A. P. Antonchick Short Review

Following this, Antonchick and Manna developed an un- I II 2 [Cu ] + (t-BuO)2 2 t-BuO-[Cu ] precedented copper-catalyzed [1+1+1] cyclotrimerization t-BuO-[CuII] cascade of acetophenone derivatives 36 under mild condi- [CuI] O OH O O tions for the stereoselective synthesis of cyclopropanes 74 Ar (Scheme 30).49 Various acetophenone derivatives 36 cover- Ar Ar t-BuOH Ar Ar 36 A B O ing an array of functional groups such as halogens, carbon- II O O [CuI] t-BuO-[Cu ] yl, sulfonamide, nitryl etc. participated in this oxidative annu- OH Ar Ar Ar Ar Ar lation affording the corresponding cyclopropanes 74 in mod- Ar CuIII O t-BuO-[CuII] O est to good yields. Importantly, heterocycle derivatives such as t-BuO E D C O

2-acetylthiophene delivered the desired product in 52% yield. I O [Cu ] t-BuO O III O t-BuO-[CuII] Cu A O Ar CuI (10 mol%) O O Ar O Ar dtbpy (20 mol%) Ar O DTBP (3 equiv) Ar Ar Ar Ar Ar F Ar GHO Ar Me PhCl, 90 °C, 5–18 h O O O Ar 36 74 O O O O t-BuO III III Ar = F Cu Cu Ar Ar O Ar OH Ar Ar Ar Me Br MeO2C I Ar Ar [Cu ] t-BuOH 74O Ar JO I O 43% 73% 88% 41% Me O O Scheme 31 Proposed mechanism for the [1+1+1] cyclotrimerization N S F S O O 43% 43% 35% 52% 5 Conclusion Scheme 30 Cu-catalyzed [1+1+1] cyclotrimerization In this review we have attempted to cover the tremen- dous advancement made since 2008 in the field of metal- On the basis of several control experiments carried out catalyzed radical coupling reactions leading to the α-func- with possible intermediates, it was established that this in- tionalization of ketones. The oxidative enolate coupling fo- triguing cyclotrimerization proceeds through the following cusing on the synthesis of 1,4-dicarbonyl compounds has steps: (i) initial dimerization of ketones to 1,4-diketones witnessed the development of novel and efficient synthetic (formation of B in Scheme 31), (ii) oxidation of 1,4-dike- methods, cross-couplings with equal stoichiometry of re- tones to but-2-ene-1,4-diones (formation of F), and (iii) an- acting partners, and highly diastereoselective transforma- nulation of but-2-ene-1,4-diones with the third equivalent tions. Besides elegant homo- and heterocoupling of eno- of acetophenone (formation of G). According to the pro- lates, powerful methods involving direct C(sp3)–H function- posed mechanism, the reaction begins with the oxidation of alization of ketones towards the synthesis of 1,4-dicarbonyl Cu(I) to a Cu(II) complex by DTBP (Scheme 31). Next, ace- compounds have emerged. tophenone 36 is oxidized by the Cu(II) species to radical A Importantly, 1,4-dicarbonyl compounds synthesized through its enol form. Following this, dimerization of A through these powerful oxidative coupling methods served leads to 1,4-ketone B, which through its enol form C is fur- as highly useful synthetic precursors for various heterocy- ther oxidized by a Cu(II) species to radical D. Radical D then clic and carbocyclic compounds. An efficient and direct ac- adds on the Cu(II) species to form organocuprate E that cess to these important molecular scaffolds via oxidative

subsequently undergoes β-hydride elimination to yield un- homocoupling of ketones or by cross-coupling between ke- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. saturated diketone F with complete trans selectivity. Addi- tones and diverse other coupling partners has recently evolved. tion of radical A to F, followed by trapping with a Cu(II) spe- These methodological advances in the field of radical cies affords organocuprate(III) intermediate H. Subsequent- oxidative coupling have enriched the repertoire of synthetic ly, H is converted into the metallacycle J through ligand tools available to synthetic chemists and should pave the exchange of copper in the enol form I. Finally, the desired way for future advancement in this important field of re- cyclopropane products 74 are obtained by the reductive elimi- search. Despite these achievements, more challenges re- nation of Cu(I), which in turn is re-oxidized to Cu(II) by DTBP. main to be addressed. Future studies should see further development of direct oxidative cross-coupling reactions that are more predictable and highly chemoselective. Further applications of radical C–H functionalization in the context of synthesis of complex molecular scaffolds would broaden the horizon in this field. There is a broad scope with regard to the development of asymmetric transformations involving CDC reactions of ketones. We are convinced that this ex-

Syn thesis S. Murarka, A. P. Antonchick Short Review

citing field of radical coupling reactions will continue to (18) You, L.; Liang, X.-T.; Xu, L.-M.; Wang, Y.-F.; Zhang, J.-J.; Su, Q.; Li, flourish and more general and useful methodologies involv- Y.-H.; Zhang, B.; Yang, S.-L.; Chen, J.-H.; Yang, Z. J. Am. Chem. Soc. ing such couplings will be developed. 2015, 137, 10120. (19) Clift, M. D.; Thomson, R. J. J. Am. Chem. Soc. 2009, 131, 14579. (20) Amaya, T.; Masuda, T.; Maegawa, Y.; Hirao, T. Chem. Commun. Funding Information 2014, 50, 2279. (21) Amaya, T.; Maegawa, Y.; Masuda, T.; Osafune, Y.; Hirao, T. J. Am. A.P.A. acknowledges the support of DFG (Heisenberg scholarship AN Chem. Soc. 2015, 137, 10072. 1064/4-1) and Boehringer Ingelheim Foundation (Plus 3).Deustche Forschungsgemenischa tf A(N 10644/-1) (22) Amaya, T.; Osafune, Y.; Maegawa, Y.; Hirao, T. Chem. Asian J. 2017, 12, 1301. (23) Mao, S.; Gao, Y.-R.; Zhang, S.-L.; Guo, D.-D.; Wang, Y.-Q. Eur. Acknowledgment J. Org. Chem. 2015, 876. (24) Mao, S.; Zhu, X.-Q.; Gao, Y.-R.; Guo, D.-D.; Wang, Y.-Q. Chem. Sandip Murarka thanks IIT Jodhpur for funding and infrastructure fa- Eur. J. 2015, 21, 11335. cilities. (25) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004. (26) Xie, J.; Huang, Z.-Z. Chem. Commun. 2010, 46, 1947. References (27) Yasu, Y.; Koike, T.; Akita, M. Chem. Commun. 2012, 48, 5355. (28) Lan, X.-W.; Wang, N.-X.; Zhang, W.; Wen, J.-L.; Bai, C.-B.; Xing, (1) Hodgson, D. M.; Charlton, A. Tetrahedron 2014, 70, 2207. Y.; Li, Y.-H. Org. Lett. 2015, 17, 4460. (2) (a) Csaky, A. G.; Plumet, J. Chem. Soc. Rev. 2001, 30, 313. (b) Guo, (29) Geibel, I.; Christoffers, J. Eur. J. Org. Chem. 2016, 918. F.; Clift, M. D.; Thomson, R. J. Eur. J. Org. Chem. 2012, 4881. (30) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein (3) Ivanoff, D.; Spasoff, A. Bull. Soc. Chim. Fr. 1935, 2, 76. J. Org. Chem. 2011, 7, 442. (b) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; (4) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 4605. Zhu, D. Chem. Rev. 2012, 112, 2208. (5) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 2912. (31) Yang, Y.; Yao, J.; Zhang, Y. Org. Lett. 2013, 15, 3206. (6) (a) Leffingwell, J. C. Chem. Commun. 1970, 357. (b) Fujii, T.; (32) Ghosh, M.; Mishra, S.; Monir, K.; Hajra, A. Org. Biomol. Chem. Hirao, T.; Ohshiro, Y. Tetrahedron Lett. 1992, 33, 5823. (c) Koichi, 2015, 13, 309. N.; Tatsuo, O.; Ken, T.; Masaharu, M. Chem. Lett. 1992, 21, 2099. (33) Ghosh, M.; Mishra, S.; Hajra, A. J. Org. Chem. 2015, 80, 5364. (d) Yasushi, K.; Koichi, N. Bull. Chem. Soc. Jpn. 1995, 68, 322. (34) Manna, S.; Antonchick, A. P. Org. Lett. 2015, 17, 4300. (7) (a) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; (35) Luo, Z.; Fang, Y.; Zhao, Y.; Liu, P.; Xu, X.; Feng, C.; Li, Z.; He, J. RSC Lei, A. Chem. Rev. 2017, 117, 9016. (b) Girard, S. A.; Knauber, T.; Adv. 2016, 6, 5436. Li, C.-J. Angew. Chem. Int. Ed. 2014, 53, 74. (c) Liu, C.; Yuan, J.; (36) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. J. Am. Chem. Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115, Soc. 2012, 134, 5766. 12138. (d) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (e) Sun, C.-L.; Li, (37) Daru, J.; Benda, Z.; Póti, Á.; Novák, Z.; Stirling, A. Chem. Eur. J. B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293. (f) Yeung, C. S.; Dong, 2014, 20, 15395. V. M. Chem. Rev. 2011, 111, 1215. (g) Yoo, W.-J.; Li, C.-J. Top. Curr. (38) Li, P.; Zhao, J.; Xia, C.; Li, F. Org. Lett. 2014, 16, 5992. Chem. 2010, 292, 281. (39) Lou, J.; Wang, Q.; Wu, K.; Wu, P.; Yu, Z. Org. Lett. 2017, 19, 3287. (8) (a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. J. Org. Chem. 1945, (40) Yi, H.; Liao, Z.; Zhang, G.; Zhang, G.; Fan, C.; Zhang, X.; Bunel, E. 10, 386. (b) Kharasch, M. S.; McBay, H. C.; Urry, W. H. J. Org. E.; Pao, C.-W.; Lee, J.-F.; Lei, A. Chem. Eur. J. 2015, 21, 18925. Chem. 1945, 10, 394. (c) Kharasch, M. S.; McBay, H. C.; Urry, W. (41) Naveen, T.; Kancherla, R.; Maiti, D. Org. Lett. 2014, 16, 5446. H. J. Am. Chem. Soc. 1948, 70, 1269. (42) Dey, A.; Ali, M. A.; Jana, S.; Hajra, A. J. Org. Chem. 2017, 82, 4812. (9) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem. Soc. 1977, (43) Wu, Y.; Huang, Z.; Luo, Y.; Liu, D.; Deng, Y.; Yi, H.; Lee, J.-F.; Pao, 99, 1487. C.-W.; Chen, J.-L.; Lei, A. Org. Lett. 2017, 19, 2330. (10) (a) Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, (44) Naveen, T.; Deb, A.; Maiti, D. Angew. Chem. Int. Ed. 2017, 56, 7083. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. 1111. Soc. 2008, 130, 11546. (45) (a) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett. (11) Casey, B. M.; Flowers, R. A. II. J. Am. Chem. Soc. 2011, 133, 11492.

2008, 10, 313. (b) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (12) Do, H.-Q.; Tran-Vu, H.; Daugulis, O. Organometallics 2012, 31, Org. Lett. 2008, 10, 5019. 7816. (46) Donthiri, R. R.; Samanta, S.; Adimurthy, S. Org. Biomol. Chem. (13) Guo, F.; Konkol, L. C.; Thomson, R. J. J. Am. Chem. Soc. 2011, 133, 2015, 13, 10113. 18. (47) (a) Chen, D. Y. K.; Pouwer, R. H.; Richard, J.-A. Chem. Soc. Rev. (14) Schmittel, M.; Burghart, A.; Malisch, W.; Reising, J.; Söllner, R. 2012, 41, 4631. (b) Tang, P.; Qin, Y. Synthesis 2012, 44, 2969. J. Org. Chem. 1998, 63, 396. (c) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Synthesis 2014, 46, (15) Clift, M. D.; Taylor, C. N.; Thomson, R. J. Org. Lett. 2007, 9, 4667. 979. (d) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem. Int. (16) Avetta, C. T.; Konkol, L. C.; Taylor, C. N.; Dugan, K. C.; Stern, C. L.; Ed. 2014, 53, 5504. Thomson, R. J. Org. Lett. 2008, 10, 5621. (48) Manna, S.; Antonchick, A. P. Angew. Chem. Int. Ed. 2015, 54, (17) Robinson, E. E.; Thomson, R. J. J. Am. Chem. Soc. 2018, 140, 1956. 14845. (49) Manna, S.; Antonchick, A. P. Angew. Chem. Int. Ed. 2016, 55, 5290.