Rh(III)-Catalyzed C–H Bond Activation for the Construction of Heterocycles with Sp3-Carbon Centers

catalysts

Review Rh(III)-Catalyzed C–H Bond Activation for the Construction of Heterocycles with sp3-Carbon Centers

1,2, 1,2, 1,2 1,2, Run Wang †, Xiong Xie †, Hong Liu and Yu Zhou * 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; [email protected] (R.W.); [email protected] (X.X.); [email protected] (H.L.) 2 School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China * Correspondence: [email protected] The authors contribute equally. † Received: 21 August 2019; Accepted: 25 September 2019; Published: 30 September 2019

Abstract: Rh(III)-catalyzed C–H activation features mild reaction conditions, good functional group tolerance, high reaction eﬃciency, and regioselectivity. Recently, it has attracted tremendous attention and has been employed to synthesize various heterocycles, such as indoles, isoquinolines, isoquinolones, pyrroles, pyridines, and polyheterocycles, which are important privileged structures in biological molecules, natural products, and agrochemicals. In this short review, we attempt to present an overview of recent advances in Rh(III)-mediated C–H bond activation to generate diverse heterocyclic scaﬀolds with sp3 carbon centers.

Keywords: C–H bond activation; Rhodium(III)-based catalysts; heterocycle with sp3 carbon centers; chirality

1. Introduction The heterocycle is one of the most important molecular scaffolds and is widely distributed in biological active molecules, agrochemicals, functional materials, and natural products [1–3]. Consequently, a large number of synthetic strategies are well-established, such as cycloaddition reaction [4], multi-component tandem reactions [5], radical cascade reactions [6], iminium ion cyclization [7], ring closing metathesis [8], and visible-light induced radical tandem reactions [9,10] among others [11–13]. However, the high-speed developing of transition-metal catalyzed C–H bond functionalization in recent years seems to offer a more direct and effective pathway to construct the intriguing heterocyclic scaffolds. Compared to classical coupling reactions, such as Suzuki coupling [14], Negishi coupling [15], Kumada coupling [16], Stille coupling [17], and Hiyama coupling [18], the transition-metal catalyzed C–H activation strategy can directly form more complicated compounds from readily accessible starting materials under mild conditions and has no relevant metal salts by-products [19–22]. Since Davies’s group [23] and Miura’s group [24,25] reported the pioneering aromatic sp2 C–H 2 bond activation by [RhCp*Cl]2, many researches involving aromatic sp C–H bond activation and further functionalization were developed to synthetize different structural motifs, especially for heterocycles, with high yields, high selectivity and broad substrate tolerance [26–28]. Recently, many excellent reviews have summarized the construction of heterocycles by different transition-metal-catalyzed C–H activation were reported, such as Pd [29], Cu [30], Ru [31], Rh [32], Ag [33], and other metals [34–38]. However, to the best of our knowledge, there is currently no review focus on Rh(III)-catalyzed heterocyclic synthesis with sp3 carbon centers. Therefore, this mini-review will focus on presenting an overview of advances in Rh(III)-catalyzed C–H activation

Catalysts 2019, 9, 823; doi:10.3390/catal9100823 www.mdpi.com/journal/catalysts Catalysts 2019, 9, 823 2 of 29 and functionalization to generate diverse heterocycles with sp3 carbon centers in the last ﬁve years. In order to discuss conveniently, these synthetic strategies will be sorted according to the size and type of the heterocycle scaﬀold.

2. Construction of Five-Member Heterocycles

2.1. Benzofuran Derivatives Among oxygen-containing heterocycles, 2,3-dihydrobenzofurans and their derivatives are the most prevalent structural cores which have been found widely in many natural products and pharmacological molecules [39–42]. As a result, the development of facial and efficient synthetic routes for the construction of these intriguing heterocycles has become an attractive goal in the synthetic community, especially in an enantioselective version. Recently, the emerging transition-metal-catalyzed C–H bond activation and followed annulation with unsaturated C–C or C–X (X=O, N et al.) bond Catalystsprovide 2019 a boulevard, 9, x FOR PEER to quicklyREVIEW synthesize these intriguing dihydrobenzofuran derivatives [43].2 of 28 In 2015, Cheng and co-workers reported a convenient and regioselective method for the synthesis 3 functionalizationof 3-coumaranones to fromgenerate readily diverse available heterocycles salicylaldehydes with sp carbon and allenes centers through in the last Rh(III)-catalyzed five years. In orderaldehyde to discuss C H activationconveniently, and these subsequent synthetic [4 + strategies1] annulation will be reactions sorted according (Scheme1 )[to 44the]. size Furthermore, and type − ofthis the catalytic heterocycle system scaffold. offers convenient access to 2-vinnyl-subsititued 3-coumaranones, for which there are currently no available methods of synthesis. Under the optical reaction conditions, the authors 2. Construction of five-member heterocycles examined the reactions of various substituted salicylaldehydes with allenes, and the results revealed that this method has good compatibilities with the electronic effect and steric hindrance. Moreover, the 2.1. Benzofuran derivatives obtained 3-coumaranones can be easily converted into their derivatives, which may be used as a useful buildingAmong block. oxygen-containing A possible mechanism heterocy basedcles, 2,3-dihydrobenzofurans on an O-hydroxyl-group-assisted and their aldehydederivatives C( aresp2) theH − mostcleavage prevalent followed structural by coupling cores with which allenes have was been proposed found (Schemewidely 2in). Themany coordination natural products of the –OHand pharmacologicalgroup on the salicylaldehydes molecules [39–42]. to the As Rh(III) a result, monomer the development complex which of facial from and the precatalystefficient synthetic Rh(III) routesdimer leadsfor the to construction an aldehyde C(of spthese2) H intriguing bond cleavage, heterocycles finally formedhas become the five-membered an attractive goal rhodacycle in the − syntheticI. Subsequently, community, Coordination especially and in an followed enantioselec insertiontive version. of allenes Recently, formed the the emerging thermodynamically transition- metal-catalyzedmore stable intermediate C–H bond IV. activation The desired and products followed are annulation delivered with by a unsaturatedβ-elimination C–C process or C–X from (X=O, the Nintermediate et al.) bond IV provide and the obtaineda boulevard Rh(I) to complex quickly is oxidizedsynthesize by these copper intriguing acetate to regeneratedihydrobenzofuran an active derivatives[Cp*Rh(III)] [43]. catalytic species and initiate the next catalytic cycle.

SchemeScheme 1. Rh(III)-catalyzedRh(III)-catalyzed the the synthesis synthesis of of 3-coumaranones. 3-coumaranones.

[Cp*RhCl2]2 Cu(OAc) O

RhX2Cp*] H X=OAc Cu(OAc)2 OH -2AcOH 1a Ph O [RhICp*] Rh Cp* O O Ph O I

C 2a 3aa O Ph Ph O H H H O Rh C RhCp* IV Ph O Cp* II O AcOH

O Rh Cp* III

Scheme 2. Proposed reaction mechanism.

Catalysts 2019, 9, x FOR PEER REVIEW 2 of 28

functionalization to generate diverse heterocycles with sp3 carbon centers in the last five years. In order to discuss conveniently, these synthetic strategies will be sorted according to the size and type of the heterocycle scaffold.

2. Construction of five-member heterocycles

2.1. Benzofuran derivatives Among oxygen-containing heterocycles, 2,3-dihydrobenzofurans and their derivatives are the most prevalent structural cores which have been found widely in many natural products and pharmacological molecules [39–42]. As a result, the development of facial and efficient synthetic routes for the construction of these intriguing heterocycles has become an attractive goal in the synthetic community, especially in an enantioselective version. Recently, the emerging transition- metal-catalyzed C–H bond activation and followed annulation with unsaturated C–C or C–X (X=O, N et al.) bond provide a boulevard to quickly synthesize these intriguing dihydrobenzofuran derivatives [43].

Catalysts 2019, 9, 823 3 of 29 Scheme 1. Rh(III)-catalyzed the synthesis of 3-coumaranones.

[Cp*RhCl2]2 Cu(OAc) O

RhX2Cp*] H X=OAc Cu(OAc)2 OH -2AcOH 1a Ph O [RhICp*] Rh Cp* O O Ph O I

C 2a 3aa O Ph Ph O H H H O Rh C RhCp* IV Ph O Cp* II O AcOH

O Rh Cp* III

Scheme 2. Proposed reaction mechanism.

Transition-metal-catalyzed C–H bond directed-functionalization has been well-established as a powerful and straightforward strategy in modern organic synthesis. However, most of these reactions require an external oxidant to regenerate catalytic species to complete the catalytic cycle. In this regard, redox-natural C–H activations utilizing internal oxidizing directing groups are more of interest and importance without the need for a stoichiometric amount of external oxidant [45,46]. In 2018, Xu and co-workers reported an eﬃcient Cp*Rh(III)-catalyzed redox-neutral C H bond activation/annulation of − N-aryloxyacetamides with alkynyloxiranes to aﬀord 2,3-dihydrobenzofurans bearing a useful exocyclic (E)-allylic alcohol and a tetra-substituted quaternary carbon center in good yields and substrate scopes (Scheme3)[ 47]. Propargylic derivatives with appropriate leaving groups have been extensively explored towards C–H bond functionalization under various transition-metal-mediated catalytic systems. The researchers adopted a strategy of combining the rich reactivity of propargylic compounds as well as the ring opening potential of oxiranes to obtain these desired compounds. According to the mechanism proposed in this article (Scheme4), [Cp*RhCl 2]2 catalyst undergoes a similar catalytic process [44] to form intermediate C and Rh(I) species, further oxidative addition of species C form a seven-number rhodacycle D which is protonated by acetic acid and followed intramolecular SN reaction to form 2,3-dihydrobenzofurans [44]. Catalysts 2019, 9, x FOR PEER REVIEW 3 of 28

In 2015, Cheng and co-workers reported a convenient and regioselective method for the synthesis of 3-coumaranones from readily available salicylaldehydes and allenes through Rh(III)- catalyzed aldehyde C−H activation and subsequent [4 + 1] annulation reactions (Scheme 1) [44]. Furthermore, this catalytic system offers convenient access to 2-vinnyl-subsititued 3-coumaranones, for which there are currently no available methods of synthesis. Under the optical reaction conditions, the authors examined the reactions of various substituted salicylaldehydes with allenes, and the results revealed that this method has good compatibilities with the electronic effect and steric hindrance. Moreover, the obtained 3-coumaranones can be easily converted into their derivatives, which may be used as a useful building block. A possible mechanism based on an O-hydroxyl-group- assisted aldehyde C(sp2)−H cleavage followed by coupling with allenes was proposed (Scheme 2). The coordination of the –OH group on the salicylaldehydes to the Rh(III) monomer complex which from the precatalyst Rh(III) dimer leads to an aldehyde C(sp2)−H bond cleavage, ﬁnally formed the ﬁve-membered rhodacycle I. Subsequently, Coordination and followed insertion of allenes formed the thermodynamically more stable intermediate IV. The desired products are delivered by a β- elimination process from the intermediate IV and the obtained Rh(I) complex is oxidized by copper acetate to regenerate an active [Cp*Rh(III)] catalytic species and initiate the next catalytic cycle. Transition-metal-catalyzed C–H bond directed-functionalization has been well-established as a powerful and straightforward strategy in modern organic synthesis. However, most of these reactions require an external oxidant to regenerate catalytic species to complete the catalytic cycle. In this regard, redox-natural C–H activations utilizing internal oxidizing directing groups are more of interest and importance without the need for a stoichiometric amount of external oxidant [45,46]. In 2018, Xu and co-workers reported an efficient Cp*Rh(III)-catalyzed redox-neutral C−H bond activation/annulation of N-aryloxyacetamides with alkynyloxiranes to afford 2,3- dihydrobenzofurans bearing a useful exocyclic (E)-allylic alcohol and a tetra-substituted quaternary carbon center in good yields and substrate scopes (Scheme 3) [47]. Propargylic derivatives with appropriate leaving groups have been extensively explored towards C–H bond functionalization under various transition-metal-mediated catalytic systems. The researchers adopted a strategy of combining the rich reactivity of propargylic compounds as well as the ring opening potential of oxiranes to obtain these desired compounds. According to the mechanism proposed in this article (Scheme 4), [Cp*RhCl2]2 catalyst undergoes a similar catalytic process[44] to form intermediate C and Rh(I) species, further oxidative addition of species C form a seven-number rhodacycle D which is Catalysts 2019 9 protonated, by, 823 acetic acid and followed intramolecular SN reaction to form 2,3-dihydrobenzofurans4 of 29 [44].

Catalysts 2019, 9, x FOR PEER REVIEW 4 of 28 Scheme 3. Rh(III)-catalyzed synthesis of 2,3-dihydrobenzofurans.

Scheme 4. The proposed reaction mechanism. Scheme 4. The proposed reaction mechanism.

InIn the the same same year, year, Zhang’s Zhang’s group group also alsoemployed employed N-aryloxyacetamidesN-aryloxyacetamides as a starting as a starting substrate substrate and coupledand coupled with propiolates with propiolates to furnish to furnish the synthesis the synthesis of benzofuran-2( of benzofuran-2(3H)-ones3H with)-ones good with yields good via yields a Rh(III)-catalyzedvia a Rh(III)-catalyzed cascade cascade[3 + 2] annulation, [3 + 2] annulation, in which NHAc in which group NHAc was groupused as was an internal used as oxidizing an internal 3 directingoxidizing group. directing The result group. enaminoate The result motif enaminoate can be motifeasily canconverted be easily into converted heterocycle into with heterocycle sp carbon with centersp3 carbon by a centersimple by oxidative a simple oxidativemanipulation manipulation (Scheme (Scheme 5) [48].5)[ Its48 ].mechanistic Its mechanistic investigations investigations by by experimentalexperimental and and density density functional functional theory theory (DFT) (DFT) studies studies suggest suggest that that a consecutive a consecutive process process of of C− CH H − bondbond functionalization/isomerization/lactonization functionalization/isomerization/lactonization is islikely likely to to be be involved involved in in this this transformation. transformation.

Scheme 5. Rh(III)-catalyzed synthesis of benzofuran-2(3H)-ones.

Catalysts 2019, 9, x FOR PEER REVIEW 4 of 28

Scheme 4. The proposed reaction mechanism.

In the same year, Zhang’s group also employed N-aryloxyacetamides as a starting substrate and coupled with propiolates to furnish the synthesis of benzofuran-2(3H)-ones with good yields via a Rh(III)-catalyzed cascade [3 + 2] annulation, in which NHAc group was used as an internal oxidizing directing group. The result enaminoate motif can be easily converted into heterocycle with sp3 carbon center by a simple oxidative manipulation (Scheme 5) [48]. Its mechanistic investigations by experimentalCatalysts 2019, 9, 823and density functional theory (DFT) studies suggest that a consecutive process of 5C of−H 29 bond functionalization/isomerization/lactonization is likely to be involved in this transformation.

Scheme 4. The proposed reaction mechanism.

In the same year, Zhang’s group also employed N-aryloxyacetamides as a starting substrate and coupled with propiolates to furnish the synthesis of benzofuran-2(3H)-ones with good yields via a Rh(III)-catalyzed cascade [3 + 2] annulation, in which NHAc group was used as an internal oxidizing directing group. The result enaminoate motif can be easily converted into heterocycle with sp3 carbon center by a simple oxidative manipulation (Scheme 5) [48]. Its mechanistic investigations by experimental and density functional theory (DFT) studies suggest that a consecutive process of C−H bond functionalization/isomerization/lactonization is likely to be involved in this transformation.

Scheme 5. Rh(III)-catalyzedRh(III)-catalyzed synthesis synthesis of of benzofuran-2(3 benzofuran-2(3HH)-ones.)-ones.

In 2019, Li’s group employed N-methoxybenzamides and 1,3-enynes as the starting materials and fulfilled a class of chemodivergent annulated coupling transformation controlled by different catalytic systems [49]. The N-annulation occurred as the major pathway to give access to lactams when a combined external oxidative system between catalytic amount copper salts and air (oxygen) was used. The chemoselectivity can be easily switched to O-annulation pathway by a simple condition modification with stoichiometric amounts of Cu(II) oxidant and NaOAc (Scheme 6). This chemodivergence, controlled by different catalytic conditions, offers an effective strategy to construct diversified benzofuranScheme or its isomer5. Rh(III)-catalyzed scaffolds. synthesis of benzofuran-2(3H)-ones.

Scheme 6. Rh(III)-catalyzed synthesis of benzofuran or its isomer scaﬀolds.

2.2. Indole Derivatives Nitrogen-containing heterocycles, especially indoles, are the most important chemical substances, which play an important role in a variety of biologically active natural and unnatural compounds [50], and also act as a versatile synthon in organic synthetic science, so it is referred as the “privileged structure”. Therefore, the synthesis and further functionalization of indoles have been a long-standing goal of research for over 100 years, and a vast number of well-established methods are available [51], many of them have been incorporated into undergraduate textbooks in the form of named reactions, for example, Bartoli indole synthesis [52], Fischer indole synthesis [53], Gassman oxindole synthesis [54], and Bischler-Moehlau indole synthesis [55]. However, compared to the synthetic strategies for aromatic indole derivatives, the synthesis for indole scaﬀolds with sp3 carbon centers, such as indolines, 1H-isoindoles, oxindoles, and isoindolin-1-ones, have emerged more recently, and mainly focus on translation-metal-mediated aromatic (sp2) C–H bond cleavage and subsequent intermolecular or intermolecular annulation cascade transformations with various π-component partners. Owing to one or more sp3 carbon centers occurring, the charity has become an inevitable challenge. However, some novel chiral catalysts were developed in recent years and brought new hope for the construction of chiral indole scaﬀolds. 1-Anminoindoline has been widely utilized as a chemical feedstock to access various skeletal motifs existed in numerous commercial drugs [56]. In 2014, Glorious and co-workers revealed an intermolecular catalytic method that can directly access 1-aminoindoline core [57]. Although C(sp2)–Rh intermediates from the insertion of alkynes into the C–Rh bond could undergo nucleophile Catalysts 2019, 9, x FOR PEER REVIEW 5 of 28

Scheme 6. Rh(III)-catalyzed synthesis of benzofuran or its isomer scaffolds.

In 2019, Li’s group employed N-methoxybenzamides and 1,3-enynes as the starting materials and fulfilled a class of chemodivergent annulated coupling transformation controlled by different catalytic systems [49]. The N-annulation occurred as the major pathway to give access to lactams when a combined external oxidative system between catalytic amount copper salts and air (oxygen) was used. The chemoselectivity can be easily switched to O-annulation pathway by a simple condition modification with stoichiometric amounts of Cu(II) oxidant and NaOAc (Scheme 6). This chemodivergence, controlled by different catalytic conditions, offers an effective strategy to construct diversified benzofuran or its isomer scaffolds.

2.2. Indole derivatives Nitrogen-containing heterocycles, especially indoles, are the most important chemical substances, which play an important role in a variety of biologically active natural and unnatural compounds [50], and also act as a versatile synthon in organic synthetic science, so it is referred as the “privileged structure”. Therefore, the synthesis and further functionalization of indoles have been a long-standing goal of research for over 100 years, and a vast number of well-established methods are available [51], many of them have been incorporated into undergraduate textbooks in the form of named reactions, for example, Bartoli indole synthesis [52], Fischer indole synthesis [53], Gassman oxindole synthesis [54], and Bischler-Moehlau indole synthesis [55]. However, compared to the synthetic strategies for aromatic indole derivatives, the synthesis for indole scaffolds with sp3 carbon centers, such as indolines, 1H-isoindoles, oxindoles, and isoindolin-1-ones, have emerged more recently, and mainly focus on translation-metal-mediated aromatic (sp2) C–H bond cleavage and subsequent intermolecular or intermolecular annulation cascade transformations with various π- component partners. Owing to one or more sp3 carbon centers occurring, the charity has become an inevitable challenge. However, some novel chiral catalysts were developed in recent years and brought new hope for the construction of chiral indole scaffolds. 1-Anminoindoline has been widely utilized as a chemical feedstock to access various skeletal motifs existed in numerous commercial drugs [56]. In 2014, Glorious and co-workers revealed an intermolecular catalytic method that can directly access 1-aminoindoline core [57]. Although C(sp2)– CatalystsRh intermediates2019, 9, 823 from the insertion of alkynes into the C–Rh bond could undergo nucleophile6 of 29 addition to C–X double bond-based (X=O,N) directing groups [58,59], the Grignard-type addition C(additionsp3)–Rh to species, C–X double generated bond-based upon alkene (X= O,N)insertion, directing to polarized groups double [58,59], bonds the Grignard-type has been a challenging addition goalC(sp 3)–Rhpresumably species, due generated to problematic upon alkene preferential insertion, toβ-hydride polarized elimination. double bonds Glorious has been et a challengingal. wonder whethergoal presumably this process due can to problematicoccur smoot preferentialhly if the additionβ-hydride step elimination. is faster than Glorious the elimination et al. wonder one. whetherFurther, thisdiazenecarboxylate process can occur is smoothly introduced if the as additiona directing step group is faster to thantrigger the a elimination new cyclative one. capture Further, approachdiazenecarboxylate where alkenes is introduced undergo as ainsertion directing followed group to triggerby intramolecular a new cyclative addition capture of approach the C(sp3 where)– Rh speciesalkenes to undergo the N=N insertion bond to followed afford diverse by intramolecular 1-aminoindolines addition without of the any C(sp external3)– Rh species oxidants to the(Scheme N=N 7).bond This to aintermolecularﬀord diverse 1-aminoindolines annulation proceeds without unde anyr externalmild conditions oxidants (Scheme(room temperature),7). This intermolecular does not requireannulation additional proceeds oxidants, under mild and conditionsdisplays a broad (room scope temperature), with respect does to not the require substituents. additional Mechanistic oxidants, studiesand displays support a broad a pathway scope with that respect proceeds to the via substituents. reversible C–H Mechanistic activation, studies alkene support insertion, a pathway and Grignard-typethat proceeds via addition.reversible C–H activation, alkene insertion, and Grignard-type addition.

Scheme 7. Rh(III)-catalyzed synthesis of diverse 1-aminoindolines. Catalysts 2019, 9, x FOR PEERScheme REVIEW 7. Rh(III)-catalyzed synthesis of diverse 1-aminoindolines. 6 of 28 Catalysts 2019, 9, x FOR PEER REVIEW 6 of 28 In 2015, Zhou’s group developed an unprecedented Rh(III)-catalyzed regioselective redox-neutral biologicallyIn 2015, importantZhou’s group 1H-benzoindolines(Scheme developed an unpreced ented8) [60]. Rh(III)-catalyzed This reaction regioselective features the redox- dual annulation reaction of 1-naphthylamine N-oxides with3 diazocompounds2 to aﬀord various biologically neutralfunctionalizationbiologically annulation important of reaction an unactivated1H -benzoindolines(Schemeof 1-naphthylamine primary C(sp N)–H-oxides bond8) [60].with and ThdiazocompoundsC(issp )–Hreaction bond withfeatures to afforddiazocarbonyl the various dual compounds.functionalizationimportant 1H -benzoindolines(Scheme of an unactivated primary8)[ 60]. C( Thissp3)–H reaction bond featuresand C(sp the2)–H dual bond functionalization with diazocarbonyl of an 3 2 compounds. unactivated primary C(sp )–H bond and C(sp )–H bond with diazocarbonyl compounds.

Scheme 8. Rh (III)-catalyzed synthesis of 1H-benzoindolines. Scheme 8. Rh (III)-catalyzed synthesis of 1H-benzoindolines. Nitrones as redox-neutral directing group are broadly applied in transition-metal-catalyzed C– H activation/couplingNitrones as redox-neutralredox-neutral with π-system directingdirecting [61,62]. groupgroup In are are 2015, broadly broadly Chang applied applied and in co-workersin transition-metal-catalyzed transition-metal-catalyzed developed a Rh(III)- C–H C– Hcatalyzedactivation activation/coupling /coupling withreaction withπ-system betweenπ-system [61, 62arylnitrones [61,62].]. In 2015, In Chang2015, and alkynesChang and co-workers andwithout co-workers developedthe requirement developed a Rh(III)-catalyzed for a externalRh(III)- oxidant,catalyzedcoupling where reactioncoupling Rhodium between reaction catalyst arylnitronesbetween not arylnitrones only and operates alkynes and in without alkynes the C−H thewithout bond requirement activation the requirement for but external also for evolve external oxidant, O- whereatomoxidant, transfer Rhodium where process. Rhodium catalyst The not catalyst protocol only operates not gives only inrise operates the to C indolineH in bond the products activationC−H bond under but activation also mild evolve reactionbutO also-atom conditionsevolve transfer O- − process.withatom goodtransfer The yields protocol process. and high gives The diastereoselectivity riseprotocol to indoline gives rise products (Schemto indoline undere 9) [63]. mildproducts It reactionis speculated under conditions mild that reaction steric with factors good conditions yields may bewithand the highgood foremost diastereoselectivity yields determinants and high diastereoselectivity of (Scheme stereoselectivity.9)[ 63]. It(Schem is Meanwhile, speculatede 9) [63]. the that It issame stericspeculated group factors used that may diazosteric be the compoundsfactors foremost may insteadbedeterminants the foremost of alkynes of determinants stereoselectivity. coupling partners of stereoselectivity. Meanwhile, to give access the Meanwhile, to same N-hydroxyindolines group the same used group diazo under used compounds diazoa similar compounds instead catalytic of systeminsteadalkynes [64].of coupling alkynes partners coupling to partners give access to give to N -hydroxyindolinesaccess to N-hydroxyindolines under a similar under catalytic a similar system catalytic [64]. system [64].

Scheme 9. Rh(III)-catalyzed synthesis of indoline. Scheme 9. Rh(III)-catalyzed synthesis of indoline. In 2018, Gulías Gulías group designeddesigned and synthesized a series of novel structurally Rh(III) complexes E possessingIn 2018, an an Gulías electron-withdrawing electron-withdrawing group designed and Cp CpE synthesized ligandligand to tobuild a build series two two of substituted novel substituted structurally indoline indoline Rh(III) products products complexes via thevia possessingannulationthe annulation anof electron-withdrawing2-alkenylnosylanilides of 2-alkenylnosylanilides Cp andE ligand and alkynes alkynes to buildwith with twomoderate moderate substituted to to good goodindoline yields yields products and and excellent via the regioselectivitiesannulation of 2-alkenylnosylanilides (Scheme 10)10)[ [65]65].. Formally, Formally, and alkynes the the protocol protocol with moderate can can serve serve to as good an allylic yields amination and excellent with accompaniedregioselectivities hydrocarbonation (Scheme 10) [65] of .the Formally, alkyne componthe protocolent. A can detailed serve mechanistic as an allylic study amination was carried with outaccompanied to illustrate hydrocarbonation that this conversion of the is alkynerelated compon to a singularent. A Rhodiumdetailed mechanistic migration with study a wassubsequent carried 1,5-out Hto shift illustrate cascade that process. this conversion is related to a singular Rhodium migration with a subsequent 1,5-H shift cascade process.

Scheme 10. Rh(III)-catalyzed synthesis of 2-substituted indoline. Scheme 10. Rh(III)-catalyzed synthesis of 2-substituted indoline. Isoindolinones, another class of indole derivative, are ubiquitous in pharmaceuticals and natural productsIsoindolinones, [66]. The most another basic class method of indole for the derivative, construction are ubiquitous of indolinones in pharmaceuticals may be [4 + 1] andannulation natural productsof arylamides [66]. withThe mostolefins basic or propargylmethod for alcohols the constr via uctionC−H bond of indolinones activation pathway.may be [4 For+ 1] example, annulation Li ofand arylamides co-workers with in 2010olefins demonstrated or propargyl Rh(III)-mediaalcohols via Cted−H C–Hbond bond activation activation pathway. to afford For example, vinylation Li andproduct co-workers and followed in 2010 by demonstratedintramolecular Rh(III)-media Michael additionted C–Hreaction bond to giveactivation the targeted to afford isoindolinone vinylation compoundsproduct and (Schemefollowed 11) by [67].intramolecular Compared Michael to the traditional addition reaction Heck coupling to give thereaction, targeted this isoindolinone protocol can toleratecompounds electron-poor (Scheme 11) olefins [67]. Comparedwhere the toformed the traditional vinylation Heck products coupling may reaction, further thisundergo protocol in-situ can tolerate electron-poor olefins where the formed vinylation products may further undergo in-situ

Catalysts 2019, 9, x FOR PEER REVIEW 6 of 28 biologically important 1H-benzoindolines(Scheme 8) [60]. This reaction features the dual functionalization of an unactivated primary C(sp3)–H bond and C(sp2)–H bond with diazocarbonyl compounds.

Scheme 8. Rh (III)-catalyzed synthesis of 1H-benzoindolines.

Nitrones as redox-neutral directing group are broadly applied in transition-metal-catalyzed C– H activation/coupling with π-system [61,62]. In 2015, Chang and co-workers developed a Rh(III)- catalyzed coupling reaction between arylnitrones and alkynes without the requirement for external oxidant, where Rhodium catalyst not only operates in the C−H bond activation but also evolve O- atom transfer process. The protocol gives rise to indoline products under mild reaction conditions with good yields and high diastereoselectivity (Scheme 9) [63]. It is speculated that steric factors may be the foremost determinants of stereoselectivity. Meanwhile, the same group used diazo compounds instead of alkynes coupling partners to give access to N-hydroxyindolines under a similar catalytic system [64].

Scheme 9. Rh(III)-catalyzed synthesis of indoline.

In 2018, Gulías group designed and synthesized a series of novel structurally Rh(III) complexes E Catalystspossessing2019, 9an, 823 electron-withdrawing Cp ligand to build two substituted indoline products via7of the 29 annulation of 2-alkenylnosylanilides and alkynes with moderate to good yields and excellent regioselectivities (Scheme 10) [65]. Formally, the protocol can serve as an allylic amination with accompaniedaccompanied hydrocarbonationhydrocarbonation ofof thethe alkynealkyne component.component. A detailed mechanistic study waswas carriedcarried outout toto illustrateillustrate thatthat thisthis conversionconversion isis relatedrelated toto aa singularsingular RhodiumRhodium migrationmigration withwith aa subsequentsubsequent 1,5-1,5-HH shiftshift cascadecascade process.process.

SchemeScheme 10.10. Rh(III)-catalyzed synthesis of 2-substituted indoline.

Isoindolinones,Isoindolinones, anotheranother classclass ofof indoleindole derivative,derivative, areare ubiquitousubiquitous inin pharmaceuticals andand naturalnatural productsproducts [[66].66]. The mostmost basicbasic methodmethod forfor thethe constructionconstruction ofof indolinonesindolinones maymay bebe [4[4 ++ 1]1] annulationannulation of arylamides with olefins or propargyl alcohols via C H bond activation pathway. For example, of arylamides with olefins or propargyl alcohols via C−−H bond activation pathway. For example, Li Liand and co-workers co-workers in in2010 2010 demonstrated demonstrated Rh(III)-media Rh(III)-mediatedted C–H C–H bond bond activation activation to to afford afford vinylationvinylation productproduct andand followedfollowed byby intramolecularintramolecular MichaelMichael additionaddition reactionreaction toto givegive the targeted isoindolinone Catalystscompoundscompounds 2019, 9 ,(Scheme x FOR PEER 11)11 REVIEW)[ [67].67]. Compared Compared to tothe the traditional traditional Heck Heck coupling coupling reaction, reaction, this thisprotocol protocol7 of can 28 cantolerate tolerate electron-poor electron-poor olefins olefins where where the the formed formed vinylation vinylation products products may may further further undergo in-situin-situ intramolecularintramolecular MichaelMichael additionaddition to to a affordfford γ -lactamsγ-lactams skeleton. skeleton. As As part part of of their their continuing continuing eff ortsefforts in the in thedevelopment development of e offfi efficientcient and and facile facile Rh(III)-based Rh(III)-based catalytic catalytic methodologies, methodologies, Li’s Li’s group group also also reported reported a anew new protocol protocol to to construct construct various variousN N-substituted-substituted isoindolinonesisoindolinones [[68],68], inin which a C C-H‒H bond cleavage of benzamide and subsequent cycloaddition coupling with propargyl alcohols as one-carbon unit were developed. Furthermore, Furthermore, Li Li and and co-workers co-workers extended extended a chemodivergent a chemodivergent annulative annulative coupling coupling to selectivelyto selectively product product γ-lactamsγ-lactams by by Rhodium(III)-mediated Rhodium(III)-mediated C C−HH bond bond cleavage cleavage and and 1,4-Rh 1,4-Rh atom − immigrationimmigration [49]. [49].

Scheme 11. Rh(III)-catalyzedRh(III)-catalyzed synthesis synthesis of isoindolinone.

In 2013, 2013, Rovis Rovis and and co-workers co-workers developed developed a anew new approach approach to to access access isoindolinones isoindolinones bearing bearing a quaternarya quaternary carbon carbon center center by byusing using diazo diazo compou compoundsnds as asone-carbon one-carbon syntho synthonsns (Scheme (Scheme 12) 12[69].)[69 A]. wideA wide range range of ofsubstrates substrates are are tolerated, tolerated, including including 1-aryl-2,2,2-tri 1-aryl-2,2,2-trifluoroethylfluoroethyl diazo diazo compounds. compounds. Mechanistic studies studies demonstrated demonstrated that that C–H C–H activation activation isis turnover-limiting turnover-limiting and and irreversible, irreversible, which which is similaris similar to the to synthesis the synthesis of some of somedihydroisoquinolones dihydroisoquinolones [70]. After [70 ].that, After other that, scientists other took scientists advantage took ofadvantage ethenesulfonyl of ethenesulfonyl fluoride [71], fluoride hydrazones [71], from hydrazones ketones fromand hydrazins ketones andin-situ hydrazins [72], α-allenols in-situ [73], [72], andα-allenols ketenimines [73], and [74] ketenimines as another [ 74co]upling as another partners coupling to synthesize partners to various synthesize isoindolinone various isoindolinone analogues, respectively.analogues, respectively.

Scheme 12. Rh(III)-catalyzedRh(III)-catalyzed synthesis of isoindolones.

In recent years, our group has been devoted to developing some highly efficient synthetic strategies to extend our heterocyclic compounds library for the screening of biologically active lead compounds [75−85]. In 2017, we built a novel isoindolone scaffold bearing a quaternary carbon via Rh(III)-catalyzed C−H bond cleavage and subsequent [4 + 1] cyclization tandem reactions between benzamides and propargyl alcohols (Scheme 13)[76]. The biggest merit of this transformation is that a novel synthetic utility of propargyl alcohols as a one-carbon synthon has been found, which can give an unusual [4 + 1] transformation. More interestingly, the target isoindolinones can be converted into four-ring scaffold isoindolo [2,1-a] quinoline derivatives. The mild reaction conditions and good substrate tolerances offer a good potential for further practical applications in future.

Scheme 13. Rh(III)-catalyzed synthesis of isoindolo[2,1-a]quinoline.

Catalysts 2019, 9, x FOR PEER REVIEW 7 of 28

intramolecular Michael addition to afford γ-lactams skeleton. As part of their continuing efforts in the development of efficient and facile Rh(III)-based catalytic methodologies, Li’s group also reported a new protocol to construct various N-substituted isoindolinones [68], in which a C‒H bond cleavage of benzamide and subsequent cycloaddition coupling with propargyl alcohols as one-carbon unit were developed. Furthermore, Li and co-workers extended a chemodivergent annulative coupling to selectively product γ-lactams by Rhodium(III)-mediated C−H bond cleavage and 1,4-Rh atom immigration [49].

Scheme 11. Rh(III)-catalyzed synthesis of isoindolinone.

In 2013, Rovis and co-workers developed a new approach to access isoindolinones bearing a quaternary carbon center by using diazo compounds as one-carbon synthons (Scheme 12) [69]. A wide range of substrates are tolerated, including 1-aryl-2,2,2-triﬂuoroethyl diazo compounds. Mechanistic studies demonstrated that C–H activation is turnover-limiting and irreversible, which is similar to the synthesis of some dihydroisoquinolones [70]. After that, other scientists took advantage of ethenesulfonyl fluoride [71], hydrazones from ketones and hydrazins in-situ [72], α-allenols [73], and ketenimines [74] as another coupling partners to synthesize various isoindolinone analogues, respectively.

Catalysts 2019, 9, 823 8 of 29

Scheme 12. Rh(III)-catalyzed synthesis of isoindolones. In recent years, our group has been devoted to developing some highly efficient synthetic strategiesIn recent to extend years, our our heterocyclic group has compounds been devoted library to developing for the screening some highly of biologically efficient synthetic active lead compoundsstrategies to [75 extend–85]. our In 2017, heterocyclic we built compounds a novel isoindolone library for scathe ffscreeningold bearing of biologically a quaternary active carbon lead via Rh(III)-catalyzedcompounds [75− C85].H In bond 2017, cleavage we built anda novel subsequent isoindolon [4e+ scaffold1] cyclization bearing tandem a quaternary reactions carbon between via − benzamidesRh(III)-catalyzed and propargyl C−H bond alcohols cleavage (Scheme and subsequent 13)[76]. The[4 + biggest1] cyclization merit oftandem this transformation reactions between is that a novelbenzamides synthetic and utilitypropargyl of propargyl alcohols (Scheme alcohols 13)[76]. as a one-carbon The biggest synthonmerit of this has transformation been found, which is that can givea novel an unusual synthetic [4 +utility1] transformation. of propargyl alcohols More interestingly, as a one-carbon the targetsynthon isoindolinones has been found, can bewhich converted can give an unusual [4 + 1] transformation. More interestingly, the target isoindolinones can be converted into four-ring scaffold isoindolo [2,1-a] quinoline derivatives. The mild reaction conditions and good into four-ring scaffold isoindolo [2,1-a] quinoline derivatives. The mild reaction conditions and good substrate tolerances offer a good potential for further practical applications in future. substrate tolerances offer a good potential for further practical applications in future.

Scheme 13. Rh(III)-catalyzed synthesis of isoindolo[2,1-a]quinoline. Catalysts 2019, 9, x FOR PEERScheme REVIEW 13. Rh(III)-catalyzed synthesis of isoindolo[2,1-a]quinoline. 8 of 28

In 2017, Loh and co-workers reported a process for the formation of isoindolinone derivatives In 2017, Loh and co-workers reported a process for the formation of isoindolinone derivatives which involved Rh(III)-mediated [4 + 1] annulation reaction utilizing α,α-difluoromethylene alkynes which involved Rh(III)-mediated [4 + 1] annulation reaction utilizing α,α-difluoromethylene alkynes as a structurally novel one-carbon synthon (Scheme 14)[86]. The 2-fold cleavage of C–F bond of as a structurally novel one-carbon synthon (Scheme 14) [86]. The 2-fold cleavage of C–F bond of α,α- α,α-difluoromethylene alkyne not only affords the targeted molecules without the need for an oxidant, difluoromethylene alkyne not only affords the targeted molecules without the need for an oxidant, but also enables a net migration of the carbon carbon triple bond. but also enables a net migration of the carbon−carbon triple bond.

Scheme 14. Rh(III)-catalyzedRh(III)-catalyzed synthesis synthesis of isoindolinones.

Actually, many of the above reports involve the formation of a quaternary carbon or a tertiary Actually, many of the above reports involve the formation of a quaternary carbon or a tertiary carbon in the process of C–H activation and/or further annulation, and indicates that the chirality of carbon in the process of C–H activation and/or further annulation, and indicates that the chirality of these intriguing heterocyclic scaffolds become an inevitable new scientific question. More recently, these intriguing heterocyclic scaffolds become an inevitable new scientific question. More recently, Wang and co-workers [87] completed a very interesting and important asymmetric synthesis of Wang and co-workers [87] completed a very interesting and important asymmetric synthesis of via alkynyl and monofluoroalkenyl monofluoroalkenyl isoindolinones via a Cp*Rh(III)-catalyzed C– C–HH activation [[86].86]. The N , authors employed N-methoxybenzamides-methoxybenzamides and andα α,α α-difluoromethylene-difluoromethylene alkynes alkyne ass as starting starting materials materials to toasymmetrically asymmetrically synthesize synthesize alkynyl alkynyl and and monofluoroalkenyl monofluoroalkenyl isoindolinones isoindolinones through through a sequence a sequence of C–H of C–Hactivation activation with awith chiral a chiral Rh(III) Rh(III) catalyst catalyst (Scheme (Sch 15eme). Meaningfully, 15). Meaningf alkynylully, alkynyl isoindolinones isoindolinones are formed are in CH3OH with high yields and excellent ee values, monofluoroalkenyl isoindolinones are afforded in formed in CH3OH with high yields and excellent ee values, monofluoroalkenyl isoindolinones are i afforded-PrCN with in i-PrCN good yields, with good regioselectivities, yields, regioselectivities, and enantioselectivities. and enantioselectivities.

Scheme 15. Chiral Cp-Rh(III)-catalyzed synthesis of isoindolinones.

2.3. Others Other nitrogen-containing nonaromatic heterocycles, such as dihydropyrrole and pyrazoline are also very valuable structural motifs in many functional molecules [88,89]. In 2013, Murakami and co- workers developed a stereoselective method to give access to trans-2,3-disubstituted 2,3- dihydropyrroles from terminal alkynes, N-sulfonyl azides and α,β-unsaturated aldehydes (Scheme 16) [90]. More recently, the same group reported that sulfonylation of 1H-tetrazoles with triflic anhydride resulted in denitrogenation to Rh(III) carbene-like species in the presence of chiral Rh(III) complex dimer. As a new type of donor/acceptor carbenoid, it is easy to react with styrene to provide 3,5-diaryl-2-pyrazolines to induce high enantioselectivity [91].

Scheme 16. Rh(III)-catalyzed synthesis of trans-2,3-disubstituted 2,3-dihydropyrroles.

Catalysts 2019, 9, x FOR PEER REVIEW 8 of 28

In 2017, Loh and co-workers reported a process for the formation of isoindolinone derivatives which involved Rh(III)-mediated [4 + 1] annulation reaction utilizing α,α-difluoromethylene alkynes asCatalysts a structurally 2019, 9, x FOR novel PEER one-carbonREVIEW synthon (Scheme 14) [86]. The 2-fold cleavage of C–F8 ofbond 28 of α,α- difluoromethylene alkyne not only affords the targeted molecules without the need for an oxidant, In 2017, Loh and co-workers reported a process for the formation of isoindolinone derivatives but also enables a net migration of the carbon−carbon triple bond. which involved Rh(III)-mediated [4 + 1] annulation reaction utilizing α,α-difluoromethylene alkynes as a structurally novel one-carbon synthon (Scheme 14) [86]. The 2-fold cleavage of C–F bond of α,α- difluoromethylene alkyne not only affords the targeted molecules without the need for an oxidant, but also enables a net migration of the carbon−carbon triple bond.

Scheme 14. Rh(III)-catalyzed synthesis of isoindolinones.

Actually, many of the above reports involve the formation of a quaternary carbon or a tertiary Scheme 14. Rh(III)-catalyzed synthesis of isoindolinones. carbon in the process of C–H activation and/or further annulation, and indicates that the chirality of these Actually,intriguing many heterocyclic of the above scaffolds reports involvebecome the an fo inevitablermation of newa quaternary scientific carbon question. or a tertiary More recently, Wangcarbon and in the co-workers process of C–H[87] activationcompleted and/or a very furt herinte annulation,resting and and important indicates that asymmetric the chirality synthesis of of alkynylthese intriguing and monofluoroalkenyl heterocyclic scaffolds isoindolinones become an inevitable via a Cp*Rh(III)-catalyzed new scientific question. C– HMore activation recently, [86]. The authorsWang and employed co-workers N-methoxybenzamides [87] completed a very and inte αresting, α-difluoromethylene and important asymmetric alkynes assynthesis starting of materials toalkynyl asymmetrically and monofluoroalkenyl synthesize alkynyl isoindolinones and monofluo via a Cp*Rh(III)-catalyzedroalkenyl isoindolinones C–H activation through [86]. a Thesequence of C–Hauthors activation employed with N-methoxybenzamides a chiral Rh(III) catalyst and α ,(Sch α-difluoromethyleneeme 15). Meaningf alkyneully,s asalkynyl starting isoindolinones materials are to asymmetrically synthesize alkynyl and monofluoroalkenyl isoindolinones through a sequence of formed in CH3OH with high yields and excellent ee values, monofluoroalkenyl isoindolinones are C–H activation with a chiral Rh(III) catalyst (Scheme 15). Meaningfully, alkynyl isoindolinones are afforded in i-PrCN with good yields, regioselectivities, and enantioselectivities. Catalystsformed2019 in ,CH9, 8233OH with high yields and excellent ee values, monofluoroalkenyl isoindolinones are 9 of 29 afforded in i-PrCN with good yields, regioselectivities, and enantioselectivities.

SchemeScheme 15. 15. Chiral Chiral Cp-Rh(III)-catalyzed Cp-Rh(III)-catalyzed synthesis synthesis of isoindolinones. of isoindolinones.

2.3.2.3. Others Others OtherOther nitrogen-containing nonaromatic nonaromatic heterocycl heterocycles,heterocycles, suches, suchassuch dihydropyrrole as dihydropyrrole and pyrazoline and pyrazoline are are alsoalso very veryvery valuable valuable structural structural structural motifs motifs motifs in manyin many in functional many functional functional molecules molecules molecules [88,89]. [88,89]. In 2013, [88 In, 89Murakami 2013,]. In Murakami 2013, and co- Murakami and co- andworkersworkers co-workers developed developed a a stereoselectivestereoselective a stereoselective method method to method giveto giveaccess to giveaccess to trans access to-2,3-disubstituted trans to -2,3-disubstitutedtrans-2,3-disubstituted 2,3- 2,3- dihydropyrroles from terminal alkynes, N-sulfonyl azides and α,β-unsaturated aldehydes (Scheme 2,3-dihydropyrrolesdihydropyrroles from from terminal terminal alkynes, alkynes, N-sulfonylN-sulfonyl azides azidesand α,β and-unsaturatedα,β-unsaturated aldehydes aldehydes (Scheme 16) [90]. More recently, the same group reported that sulfonylation of 1H-tetrazoles with triflic (Scheme16) [90]. 16More)[90 ].recently, More recently, the same the samegroup group reported reported that that sulfonylation sulfonylation of of1H 1H-tetrazoles-tetrazoles with with triflic triﬂic anhydride resulted in denitrogenation to Rh(III) carbene-like species in the presence of chiral Rh(III) anhydride resulted in denitrogenation to Rh(III) carbene-like species in the presence of chiral Rh(III) anhydridecomplex dimer. resulted As a innew deni typetrogenation of donor/acceptor to Rh(III) carbenoid, carbene-like it is easy spec to reacties in with the styrenepresence to provideof chiral Rh(III) complex3,5-diaryl-2-pyrazolines dimer. As a new to induce type of high donor/acceptor donor enantioselectivity/acceptor carbenoid, [91]. it is easy to react with styrene to provide 3,5-diaryl-2-pyrazolines to induce high enantioselectivity [91]. Catalysts3,5-diaryl-2-pyrazolines 2019, 9, x FOR PEER REVIEW to induce high enantioselectivity [91]. 9 of 28

3. Construction of six-member heterocycles

3.1. Nitrogen heterocycles The synthesis of nitrogen-containing heterocycles has attracted considerable attention in the synthetic communityScheme because 16. Rh(III)-catalyzed of the important synthesis role of transin pharmaceutical-2,3-disubstituted components. 2,3-dihydropyrroles. Among them, pyridines represent one of the most prevalent scaffolds encountered in medicinal chemistry. In 2015, Scheme 16. Rh(III)-catalyzed synthesis of trans-2,3-disubstituted 2,3-dihydropyrroles. the group of RovisScheme reported 16. Rh(III)-catalyzed that α,β-unsaturated synthesis oxime of pivalatestrans-2,3-disubstituted could undergo 2,3-dihydropyrroles.reversible C(sp2)−H insertion with cationic Rh(III) complexes to furnish five-member metallacycles, which could further 3. Construction of Six-Member Heterocycles be converted into 2,3-dihydropyridine products in good yields via an irreversible migratory insertion and3.1. reductive Nitrogen elimination Heterocycles under the presence of 1,1-disubstituted olefins (Scheme 17) [92]. More importantly, the 2,3-dihydropyridines can be used to convert into piperidines by catalytic hydrogenationThe synthesis which are of important nitrogen-containing structural scaffolds heterocycles of pharmaceuticals. has attracted considerable attention in the syntheticIsoquinolinones, community which because act as a ofvery the common important class roleof heterocyclic in pharmaceutical skeletons, components.is widely used in Among them, thepyridines medicinal chemistry represent and one agrochemical of the most industries. prevalent [93–95]. scaff Theyolds provide encountered a very perfect in medicinal motivation chemistry. In for2015, organic the chemists group to of develop Rovis reporteda large number that αof,β sy-unsaturatednthetic strategies oxime to build pivalates them [95]. could In 2013, undergo by reversible utilizingC(sp2) differentH insertion directing with groups, cationic Rovis’s Rh(III) group complexes reported to three furnish distinct five-member Rh(III)-catalyzed metallacycles, reaction which could strategies− with tethered olefin-containing benzamides (Scheme 18) [96]. Hydroarylation, further be converted into 2,3-dihydropyridine products in good yields via an irreversible migratory amidoarylation, and dehydrogenative Heck type products can be obtained based on the type of insertion and reductive elimination under the presence of 1,1-disubstituted olefins (Scheme 17)[92]. amide substrate used. A wide range of tethered alkenes can cyclize to equip six-member products in goodMore yields. importantly, Furthermore, the this 2,3-dihydropyridines reaction showed high can diastereoselectivity be used to convert in the into amidoarylation piperidines by catalytic processhydrogenation of a substrate which containing are important a pre-existing structural stereocenter. scaffolds of pharmaceuticals.

Scheme 17. Rh(III)-catalyzed synthesis of piperidines. Scheme 17. Rh(III)-catalyzed synthesis of piperidines.

Isoquinolinones, which act as a very common class of heterocyclic skeletons, is widely used in the medicinal chemistry and agrochemical industries. [93–95]. They provide a very perfect motivation for

Scheme 18. Rh(III)-catalyzed intramolecular hydroarylation.

In 2017, Wang and co-workers developed the Rh(III)-catalyzed C–H bond activation/annulations of ketenimines with N-methoxybenzamides to prepare isoquinolinones and isoindolinones (Scheme 19) [97]. The molecular structure of the ketenimine component was found to determine the reaction outcomes. By using the β-alkyl substituted ketenimines, the reaction afforded 3-iminoisoquinolin- 1(2H)-ones in a formal [4 + 2] annulation manner, while the β-ester group substituted ketenimines furnished 3-aminoisoindolin-1-ones in a formal [4 + 1] annulation manner. Furthermore, the synthesized [4 + 2] products could be converted to benzo[4, 5] imidazo [1, 2-b]isoquinolin-11-ones by an intramolecular Cu-catalyzed C–N bond coupling, which then could be directly converted into heterocyclic products which are important in medicinal chemistry.

Catalysts 2019, 9, x FOR PEER REVIEW 9 of 28

3. Construction of six-member heterocycles

3.1. Nitrogen heterocycles The synthesis of nitrogen-containing heterocycles has attracted considerable attention in the synthetic community because of the important role in pharmaceutical components. Among them, pyridines represent one of the most prevalent scaffolds encountered in medicinal chemistry. In 2015, the group of Rovis reported that α,β-unsaturated oxime pivalates could undergo reversible C(sp2)−H insertion with cationic Rh(III) complexes to furnish five-member metallacycles, which could further be converted into 2,3-dihydropyridine products in good yields via an irreversible migratory insertion and reductive elimination under the presence of 1,1-disubstituted olefins (Scheme 17) [92]. More importantly, the 2,3-dihydropyridines can be used to convert into piperidines by catalytic hydrogenation which are important structural scaffolds of pharmaceuticals. Isoquinolinones, which act as a very common class of heterocyclic skeletons, is widely used in the medicinal chemistry and agrochemical industries. [93–95]. They provide a very perfect motivation for organic chemists to develop a large number of synthetic strategies to build them [95]. In 2013, by utilizing different directing groups, Rovis’s group reported three distinct Rh(III)-catalyzed reaction strategies with tethered olefin-containing benzamides (Scheme 18) [96]. Hydroarylation, amidoarylation, and dehydrogenative Heck type products can be obtained based on the type of amide substrate used. A wide range of tethered alkenes can cyclize to equip six-member products in good yields. Furthermore, this reaction showed high diastereoselectivity in the amidoarylation process of a substrate containing a pre-existing stereocenter. Catalysts 2019, 9, 823 10 of 29 organic chemists to develop a large number of synthetic strategies to build them [95]. In 2013, by utilizing diﬀerent directing groups, Rovis’s group reported three distinct Rh(III)-catalyzed reaction strategies with tethered oleﬁn-containing benzamides (Scheme 18)[96]. Hydroarylation, amidoarylation, and dehydrogenative Heck type products can be obtained based on the type of amide substrate used. A wide range of tethered alkenes can cyclize to equip six-member products in good yields. Furthermore, this reaction showed high diastereoselectivity in the amidoarylation process of a substrate containing a pre-existingScheme stereocenter.17. Rh(III)-catalyzed synthesis of piperidines.

Catalysts 2019, 9, x FOR PEERScheme REVIEW 18. Rh(III)-catalyzed intramolecular hydroarylation. 10 of 28 Scheme 18. Rh(III)-catalyzed intramolecular hydroarylation. In 2017, Wang and co-workers developed the Rh(III)-catalyzed C–H bond activation/annulations of keteniminesIn 2017, Wang with and co-workersN-methoxybenzamides developed the to Rh prepare(III)-catalyzed isoquinolinones C–H bond activation/annulations and isoindolinones (Schemeof ketenimines 19)[97 with]. The N-methoxybenzamides molecular structure ofto theprepare ketenimine isoquinolinones component and was isoindolinones found to determine (Scheme the19) [97]. reaction The molecular outcomes. structure By using of the the ketenimineβ-alkyl substituted component ketenimines,was found to determine the reaction the areactionfforded 3-iminoisoquinolin-1(2outcomes. By using theH )-onesβ-alkyl in substituted a formal [4 + ketenimines,2] annulation the manner, reaction while afforded the β-ester 3-iminoisoquinolin- group substituted ketenimines1(2H)-ones in furnished a formal3-aminoisoindolin-1-ones [4 + 2] annulation manner, in awhile formal the [4 β+-ester1] annulation group substituted manner. Furthermore,ketenimines Scheme 19. Rh(III)-catalyzed synthesis of isoquinolinones and isoindolinones. thefurnished synthesized 3-aminoisoindolin-1-ones [4 + 2] products could in be converteda formal to[4 benzo+ 1] [annulation4,5] imidazo ma [1,nner. 2-b]isoquinolin-11-ones Furthermore, the synthesized [4 + 2] products could be converted to benzo[4, 5] imidazo [1, 2-b]isoquinolin-11-ones by by anIn intramolecular addition, Wang’s Cu-catalyzed group constructed C–N bondcoupling, four types which of thenfluorine could substituted be directly isoquinolinone converted into Catalystsan intramolecular 2019, 9, x FOR Cu-catalyzedPEER REVIEW C–N bond coupling, which then could be directly converted10 ofinto 28 scaffoldsheterocyclic via products Rh(III)-catalyzed which are importantC–H bond in activation medicinal chemistry.of arenes and further coupling with 2,2- heterocyclic products which are important in medicinal chemistry. difluorovinyl tosylate [98], which is a very interesting and important work because incorporating fluorinated groups and fluorine atoms is a common strategy for drug modification. The unique properties imparted by fluorine atom have rendered it a popular element in functional molecules (Scheme 20). Ketenes (R1R2C=C=O) are highly reactive reagents that have been widely used in the synthesis of complex carbonyl compounds in metal-catalyzed addition and cross-coupling reactions [99]. Li’s Scheme 19. Rh(III)-catalyzed synthesis of isoquinolinones and isoindolinones. group in 2018 realizedScheme 19. a mildRh(III)-catalyzed and redox-neutral synthesis Rh(III)-catalyzedof isoquinolinones and[4 + isoindolinones.2] annulation of O-pivaloyl oximesIn addition,with ketenes Wang’s to isoquinolin-4(3 group constructedH)-ones four typeswhich of is fluorine also an substituted important isoquinolinoneprivileged structure scaffolds in In addition, Wang’s group constructed four types of fluorine substituted isoquinolinone medicinalvia Rh(III)-catalyzed chemistry [99], C–H in bond which activation the N-OPiv of arenesplayed anda key further role that coupling not only with acts 2,2-difluorovinyl as an oxidizing scaffolds via Rh(III)-catalyzed C–H bond activation of arenes and further coupling with 2,2- grouptosylate but [98 also], which offers is acoordinati very interestingon saturation and important to inhibit work proton becauseolysis. incorporating The DFT mechanism fluorinated studies groups difluorovinyl tosylate [98], which is a very interesting and important work because incorporating suggestand fluorine that atomsthe C− isN abond common coupling/N strategy−O for bond drug cleavage modification. occurs The via uniquea concerted properties all-Rh(III) imparted process by fluorinated groups and fluorine atoms is a common strategy for drug modification. The unique (Schemefluorine atom21). have rendered it a popular element in functional molecules (Scheme 20). properties imparted by fluorine atom have rendered it a popular element in functional molecules (Scheme 20). Ketenes (R1R2C=C=O) are highly reactive reagents that have been widely used in the synthesis of complex carbonyl compounds in metal-catalyzed addition and cross-coupling reactions [99]. Li’s group in 2018 realized a mild and redox-neutral Rh(III)-catalyzed [4 + 2] annulation of O-pivaloyl oximes with ketenes to isoquinolin-4(3H)-ones which is also an important privileged structure in medicinal chemistry [99], in which the N-OPiv played a key role that not only acts as an oxidizing Scheme 20. Rh(III)-catalyzed C–H activation of arenes. group but also offers coordination saturation to inhibit protonolysis. The DFT mechanism studies suggestKetenes that (Rthe1R C2C−N= Cbond=O) arecoupling/N highly reactive−O bond reagents cleavage that occurs have been via a widely concerted used all-Rh(III) in the synthesis process of complex(Scheme carbonyl21). compounds in metal-catalyzed addition and cross-coupling reactions [99]. Li’s group in 2018 realized a mild and redox-neutral Rh(III)-catalyzed [4 + 2] annulation of O-pivaloyl oximes with ketenes to isoquinolin-4(3H)-ones which is also an important privileged structure in medicinal chemistry [99], in which the N-OPiv played a key role that not only acts as an oxidizing group but also Scheme 21. Rh(III)-catalyzed synthesis of isoquinolin-4(3H)-ones.

Assembling a heterocyclic motif with other heterocyles into polycyclic fused-heterocycles is an Scheme 20. Rh(III)-catalyzed C–H activation of arenes. important tactic to discover novel biological active molecules for medicinal chemistry. In 2014, Lin’s group reported two tunable arylative cyclizations of cyclohexadienone-containing 1,6-enynes with O-substituted N-hydroxybenzamides by using Rh(III)-catalyzed C−H bond activation (Scheme 22) [100]. In this transformation, different directing group, such as O-Piv and O-Me, can selectively build tetracyclic isoquinolones through an N-Michael addition process or hydrobenzofurans through a C- Michael addition process. It is a pioneering example of a Rh(III)-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm of Cp*Rh(III)-catalyzed C−H bond activation cascade reactions.Scheme 21. Rh(III)-catalyzed synthesis of isoquinolin-4(3H)-ones.

Assembling a heterocyclic motif with other heterocyles into polycyclic fused-heterocycles is an important tactic to discover novel biological active molecules for medicinal chemistry. In 2014, Lin’s group reported two tunable arylative cyclizations of cyclohexadienone-containing 1,6-enynes with O-substituted N-hydroxybenzamides by using Rh(III)-catalyzed C−H bond activation (Scheme 22) [100]. In this transformation, different directing group, such as O-Piv and O-Me, can selectively build tetracyclic isoquinolones through an N-Michael addition process or hydrobenzofurans through a C- Michael addition process. It is a pioneering example of a Rh(III)-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm of Cp*Rh(III)-catalyzed C−H bond activation cascade reactions.

Catalysts 2019, 9, x FOR PEER REVIEW 10 of 28

Scheme 19. Rh(III)-catalyzed synthesis of isoquinolinones and isoindolinones.

In addition, Wang’s group constructed four types of fluorine substituted isoquinolinone scaffolds via Rh(III)-catalyzed C–H bond activation of arenes and further coupling with 2,2- difluorovinyl tosylate [98], which is a very interesting and important work because incorporating fluorinated groups and fluorine atoms is a common strategy for drug modification. The unique properties imparted by fluorine atom have rendered it a popular element in functional molecules (Scheme 20). Ketenes (R1R2C=C=O) are highly reactive reagents that have been widely used in the synthesis of complex carbonyl compounds in metal-catalyzed addition and cross-coupling reactions [99]. Li’s group in 2018 realized a mild and redox-neutral Rh(III)-catalyzed [4 + 2] annulation of O-pivaloyl oximes with ketenes to isoquinolin-4(3H)-ones which is also an important privileged structure in medicinal chemistry [99], in which the N-OPiv played a key role that not only acts as an oxidizing group but also offers coordination saturation to inhibit protonolysis. The DFT mechanism studies suggest that the C−N bond coupling/N−O bond cleavage occurs via a concerted all-Rh(III) process (Scheme 21).

Catalysts 2019, 9, 823 11 of 29 oﬀers coordination saturation to inhibit protonolysis. The DFT mechanism studies suggest that the C N bond coupling/N OScheme bond cleavage 20. Rh(III)-catalyzed occurs via aC–H concerted activation all-Rh(III) of arenes. process (Scheme 21). − −

Scheme 21. Rh(III)-catalyzedRh(III)-catalyzed synthesis of isoquinolin-4(3 H)-ones.)-ones.

Assembling a heterocyclic motif with other heterocyles into polycyclic fused-heterocycles is an CatalystsAssembling 2019, 9, x FOR a heterocyclicPEER REVIEW motif with other heterocyles into polycyclic fused-heterocycles11 isof an28 importantimportant tactic tactic to to discover novel novel biological biological active active molecules molecules for for medicinal medicinal chemistry. chemistry. In 2014, Lin’s group reported two tunable arylative cyclizations of cyclohexadienone-containingcyclohexadienone-containing 1,6-enynes with O-substituted NN-hydroxybenzamides-hydroxybenzamides by by using using Rh(III)-catalyzed Rh(III)-catalyzed C HC− bondH bond activation activation (Scheme (Scheme 22)[100 22)]. − [100].In this In transformation, this transformation, diﬀerent different directing directing group, group, such such as asO -PivO-Piv and andO O-Me,-Me, can can selectivelyselectively build tetracyclic isoquinolones isoquinolones through through an an NN-Michael-Michael addition addition process process or orhydrobenzofurans hydrobenzofurans through through a C a- MichaelC-Michael addition addition process. process. It Itis isa apioneering pioneering example example of of a a Rh(III)-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm of Cp*Rh(III)-catalyzed CC−H bond − activationCatalysts 2019 cascade , 9, x FOR reactions. PEER REVIEW 11 of 28

Scheme 22. Rh(III)-catalyzed arylative cyclization reaction of 1,6-enynes.

After that, Li’s group in 2017 exploited the similar 1,6-enynes as the starting substrate, and realize a C–H activation of indoles by using Rh(III) catalyst to afford intriguing [6,5]-fused heterocycles, in which the alkyne insertion follows 2,1-regioselectivity with a subsequent type-I intramolecular Diels–Alder reaction (IMDA) (Scheme 23) [101]. In 2015, Saa´ group employed arylguanidines, whose guanidine group can be used as an excellent directing group, and alkynes as the starting materials to fulfil a [5 + 1] oxidative Scheme 22. Rh(III)-catalyzed arylative cyclization reaction of 1,6-enynes. cycloaddition by SchemeRh(III)-catalyst 22. Rh(III)-catalyzed to give C‐4arylative disubstituted cyclization 1,4-dihydroquinazolin-2-amines reaction of 1,6-enynes. [102], in which quinazoline ring is a classic privileged structural unit that is found in many natural products AfterAfter that,that, Li’s Li’s group group in in 2017 2017 exploited exploited the similarthe similar 1,6-enynes 1,6-enynes as the as starting the starting substrate, substrate, and realize and and pharmaceuticals (Scheme 24). This reaction tolerated a broad range of functional groups in both arealize C–H activationa C–H activation of indoles of by indoles using Rh(III)by using catalyst Rh(III) to acatalystfford intriguing to afford [6,5]-fused intriguing heterocycles, [6,5]-fused the guanidine and alkyne partners, and it also gave an easy access to gain relevant functional inheterocycles, which the alkynein which insertion the alkyne follows insertion 2,1-regioselectivity follows 2,1-regioselectivity with a subsequent with type-I a subsequent intramolecular type-I heterocycles containing the guanidine moiety. Diels–Alderintramolecular reaction Diels–Alder (IMDA) reaction (Scheme (IMDA) 23)[101 (Scheme]. 23) [101]. In 2015, Saa´ group employed arylguanidines, whose guanidine group can be used as an excellent directing group, and alkynes as the starting materials to fulfil a [5 + 1] oxidative cycloaddition by Rh(III)-catalyst to give C‐4 disubstituted 1,4-dihydroquinazolin-2-amines [102], in which quinazoline ring is a classic privileged structural unit that is found in many natural products and pharmaceuticals (Scheme 24). This reaction tolerated a broad range of functional groups in both the guanidine and alkyne partners, and it also gave an easy access to gain relevant functional heterocycles containing the guanidine moiety. Scheme 23. Rh(III)-catalyzedRh(III)-catalyzed C–H C–H bond bond activation to afford afford fused cycles. In 2015, Saa´ group employed arylguanidines, whose guanidine group can be used as an excellent directing group, and alkynes as the starting materials to fulfil a [5 + 1] oxidative cycloaddition by

SchemScheme 24. Rh(III)-catalyzed23. Rh(III)-catalyzed C–H C–H activation bond activation of [5 + 1] oxidativeto afford fusedcycloaddition. cycles.

3.2. Oxygen heterocycles Chromenes has been characterized as a class of structural cores that is ubiquitously presented in various naturally compounds and it plays an important role in pharmaceutical components with a broad spectrum of applications [103,104]. In 2015, Gulías’s group described a new Rh(III)-catalyzed oxidative annulation formally involving the cleavage of the C–H and O–H bond of 2-alkenylphenols to construct verySchem valuable 24. Rh(III)-catalyzed 2,2-disubstituted C–H 2H activation-chromenes of [5 [105], + 1] oxidative in which cycloaddition. the process is a simple and atom-economical [5 + 1] heteroannulation involving the cleavage of one C–H bond of the alkenyl moiety3.2. Oxygen and heterocyclesthe participation of the allene as a one-carbon cycloaddition partner. The mechanism Chromenes has been characterized as a class of structural cores that is ubiquitously presented in various naturally compounds and it plays an important role in pharmaceutical components with a broad spectrum of applications [103,104]. In 2015, Gulías’s group described a new Rh(III)-catalyzed oxidative annulation formally involving the cleavage of the C–H and O–H bond of 2-alkenylphenols to construct very valuable 2,2-disubstituted 2H-chromenes [105], in which the process is a simple and atom-economical [5 + 1] heteroannulation involving the cleavage of one C–H bond of the alkenyl moiety and the participation of the allene as a one-carbon cycloaddition partner. The mechanism

Catalysts 2019, 9, x FOR PEER REVIEW 11 of 28

Scheme 22. Rh(III)-catalyzed arylative cyclization reaction of 1,6-enynes.

Catalysts 2019, 9, 823 12 of 29

Rh(III)-catalyst to give C-4 disubstituted 1,4-dihydroquinazolin-2-amines [102], in which quinazoline ring is a classic privileged structural unit that is found in many natural products and pharmaceuticals (Scheme 24). This reaction tolerated a broad range of functional groups in both the guanidine and alkyne partners, and it also gave an easy access to gain relevant functional heterocycles containing the guanidine moiety.Scheme 23. Rh(III)-catalyzed C–H bond activation to afford fused cycles.

SchemeSchem 24. 24. Rh(III)-catalyzedRh(III)-catalyzed C–H C–H activation activation of of [5 [5 ++ 1]1] oxidative oxidative cycloaddition. cycloaddition.

3.2. Oxygen Oxygen heterocycles Heterocycles Chromenes has been characterized as a class of structural cores that is ubiquitously ubiquitously presented in various naturally compounds and it plays an important role in pharmaceutical components with a broad spectrum of applications [103,104]. [103,104]. In 20 2015,15, Gulías’s Gulías’s group descri describedbed a new Rh(III)-catalyzed oxidative annulation formallyformally involvinginvolving the the cleavage cleavage of of the the C–H C–H and and O–H O–H bond bond of of 2-alkenylphenols 2-alkenylphenols to toconstruct construct very very valuable valuable 2,2-disubstituted 2,2-disubstituted 2 H2H-chromenes-chromenes [ 105[105],], in in which which the the processprocess isis aa simple and atom-economical [5 [5 + 1]1] heteroannulation heteroannulation involvin involvingg the the cleavage cleavage of of one one C–H C–H bond bond of the alkenyl moietyCatalysts andand 2019 thethe, participation9 ,participation x FOR PEER REVIEW of of the the allene allene as aas one-carbon a one-carbon cycloaddition cycloaddition partner. partner. The mechanismThe mechanism12 of 28study shows that this transformation proceeds through an intriguing sequential mechanism involving an initialstudy Rh(III)-catalyzed shows that this addition transformation followed proceeds by a [1 ,7through] sigmatropic an intriguing hydrogen sequential shift and mechanism a 6π-electron electrocyclicinvolving ring an initial closure Rh(III)-catalyzed (Scheme 25). addition followed by a [1,7] sigmatropic hydrogen shift and a 6π-electron electrocyclic ring closure (Scheme 25).

SchemeScheme 25. 25.Rh(III)-catalyzed Rh(III)-catalyzed oxidativeoxidative annulation annulation for for the the synthesis synthesis of chromenes. of chromenes.

It is well known that cyclopropenes are often used as vinyl metal carbene precursors because of their highly strained unsaturated properties which are suitable as three-carbon synthons for organic synthesis. In 2014, Wang and co-workers used cyclopropenes as the first reported three-carbon units to synthesize 2H-chromenes through a Rh(III)-catalyzed C–H bond activation strategy (Scheme 26) [106]. The reaction features mild reaction conditions at room temperature and does not need external oxidants with a good substrate tolerance and good to excellent yields. Similarly, fused-chromene polycyclic scaffolds are intriguing privileged skeletons in many natural products and pharmaceuticals. The approaches to access them via transition-metal-catalyzed C–H bond activation are particularly impressive, because these products are highly congested scaffolds difficult to access through traditional methods. Zhang’s group in 2018 developed an Rh(III)- catalyzed C−H bond activation strategy to assemble pyrazolones with 1,6-enynes to access fused- chromene scaffolds (Scheme 27) [107]. This cascade reaction ranged a broad substrate scope in high regioselectivity and stereospecificity and furnished three new chemical bonds and four chiral centers in a single operation. More importantly, a variety of functional transformations of the target product were further conducted to give new polycyclic derivatives. In 2018, our group achieved a synthesis of diversified substituted benzo[de]chromenes by a Rh(III)-catalyzed C–H activation of benzoylacetonitriles in coupling with diazo compounds with a one-pot two cascade formal [4 + 2] cycloaddition with two-fold diazo compound (Scheme 28) [77]. More interestingly, controlling the reaction conditions could selectively prepare the synthesis of fused benzo[de]chromenes and their decarboxylation products. Meanwhile, this transformation has a wide range of substrates, good yields, and high regioselectivity.

Catalysts 2019, 9, 823 13 of 29

Scheme 26. TheThe Synthesis Synthesis of 2 H-chromenes.-chromenes.

Similarly, fused-chromene polycyclic scaffolds are intriguing privileged skeletons in many natural Catalysts 2019, 9, x FOR PEER REVIEW 13 of 28 products and pharmaceuticals. The approaches to access them via transition-metal-catalyzed C–H bond activation are particularly impressive, because these products are highly congested scaffolds difficult to access through traditional methods. Zhang’s group in 2018 developed an Rh(III)-catalyzed C H − bond activation strategy to assemble pyrazolones with 1,6-enynes to access fused-chromene scaffolds (Scheme 27)[107]. This cascade reaction ranged a broad substrate scope in high regioselectivity and stereospecificity and furnished three new chemical bonds and four chiral centers in a single operation. More importantly, a variety of functional transformations of the target product were further conducted to give new polycyclic derivatives.Scheme 26. The Synthesis of 2H-chromenes.

Scheme 27. The synthesis of fused-chromene scaffolds.

Scheme 27. The synthesis of fused-chromene scaﬀolds. Scheme 27. The synthesis of fused-chromene scaffolds. In 2018, our group achieved a synthesis of diversiﬁed substituted benzo[de]chromenes by a Rh(III)-catalyzed C–H activation of benzoylacetonitriles in coupling with diazo compounds with a Scheme 28. The synthesis of substituted benzo[de]chromenes. one-pot two cascade formal [4 + 2] cycloaddition with two-fold diazo compound (Scheme 28)[77]. More interestingly, controlling the reaction conditions could selectively prepare the synthesis of fused Similarly, Li’s group also finished a Rh(III)-catalyzed C–H activation of benzoylacetonitriles and benzo[de]chromenes and their decarboxylation products. Meanwhile, this transformation has a wide further coupled with sulfoxonium ylides, an important carbene source, to give benzo[de]chromenes range of substrates, good yields, and high regioselectivity. in 2018 with good yields and tolerances (Scheme 29).[108]

Scheme 28. The synthesis of substituted benzo[de]chromenes.

Similarly, Li’s group alsoScheme finished 29. Thea Rh(III)-catalyzed synthesis of benzo[ C–Hde]chromenes. activation of benzoylacetonitriles and further coupled with sulfoxonium ylides, an important carbene source, to give benzo[de]chromenes in4. Construction2018 with good of yieldsseven-member and tolerances heterocycles (Scheme 29).[108] Seven-member heterocyclic scaffolds, especially azepines or their derivatives have attracted considerable attention by virtue of their interesting biological properties. [109,110]. In 2015, Li’s group accomplished the C–H bond activation of 4-aryl-1-tosyl-1,2,3-triazoles to further perform a [3 + 2]/[5 + 2] annulation with internal alkynes to effectively construct indeno[1,7-cd]azepine scaffold by a Rh(III)-catalyst (Scheme 30) [111]. This reaction features a [3 + 2]/[5 + 2] annulation through dual C– H functionalization and is the first straightforward procedure for the synthesis of the indeno[1,7- cd]azepine skeleton with goodScheme substrate 29. The tolerances synthesis ofand benzo[ selectivity.de]chromenes.

4. Construction of seven-member heterocycles Seven-member heterocyclic scaffolds, especially azepines or their derivatives have attracted considerable attention by virtue of their interesting biological properties. [109,110]. In 2015, Li’s group accomplished the C–H bond activation of 4-aryl-1-tosyl-1,2,3-triazoles to further perform a [3 + 2]/[5 + 2] annulation with internal alkynes to effectively construct indeno[1,7-cd]azepine scaffold by a Rh(III)-catalyst (Scheme 30) [111]. This reaction features a [3 + 2]/[5 + 2] annulation through dual C– H functionalization and is the first straightforward procedure for the synthesis of the indeno[1,7- cd]azepine skeleton with good substrate tolerances and selectivity.

Catalysts 2019, 9, x FOR PEER REVIEW 13 of 28 Catalysts 2019, 9, x FOR PEER REVIEW 13 of 28

Scheme 26. The Synthesis of 2H-chromenes. Scheme 26. The Synthesis of 2H-chromenes.

Catalysts 2019, 9, 823 14 of 29 Scheme 27. The synthesis of fused-chromene scaffolds. Scheme 27. The synthesis of fused-chromene scaffolds.

SchemeScheme 28. 28. TheThe synthesissynthesis ofof substitutedsubstituted benzo[benzo[dede]chromenes.]chromenes. Scheme 28. The synthesis of substituted benzo[de]chromenes. Similarly, Li’s group also finished ﬁnished a Rh(III)-catalyzed C–H activation of benzoylacetonitriles and Similarly, Li’s group also finished a Rh(III)-catalyzed C–H activation of benzoylacetonitriles and further coupled withwith sulfoxoniumsulfoxonium ylides,ylides, an an important important carbene carbene source, source, to to give give benzo[ benzo[de]chromenesde]chromenes in further coupled with sulfoxonium ylides, an important carbene source, to give benzo[de]chromenes in2018 2018 with with good good yields yields and an tolerancesd tolerances (Scheme (Scheme 29 )[29).[108]108]. in 2018 with good yields and tolerances (Scheme 29).[108]

Scheme 29. The synthesis of benzo[de]chromenes. Scheme 29. The synthesis of benzo[ de]chromenes. 4. Construction Construction of of seve Seven-Membern-member heterocycles Heterocycles 4. Construction of seven-member heterocycles Seven-member heterocyclic heterocyclic scaffolds, scaffolds, especially azepines or their derivatives have attracted Seven-member heterocyclic scaffolds, especially azepines or their derivatives have attracted considerable attention attention by by virtue virtue of oftheir their interesting interesting biological biological properties. properties. [109,110]. [109,110 In 2015,]. In Li’s 2015, group Li’s considerable attention by virtue of their interesting biological properties. [109,110]. In 2015, Li’s group accomplishedgroup accomplished the C–H the bond C–H activation bond activation of 4-aryl-1-tosyl-1,2,3-triazoles of 4-aryl-1-tosyl-1,2,3-triazoles to further to further perform perform a [3 + a2]/[5 [3 + accomplished the C–H bond activation of 4-aryl-1-tosyl-1,2,3-triazoles to further perform a [3 + 2]/[5 +2] /2][5 annulation+ 2] annulation with with internal internal alkynes alkynes to effectively to effectively construct construct indeno[1,7- indeno[1,7-cdcd]azepine]azepine scaffold scaffold by by a + 2] annulation with internal alkynes to effectively construct indeno[1,7-cd]azepine scaffold by a Rh(III)-catalyst (Scheme 3030))[ [111].111]. ThisThis reactionreaction features features a a [3 [3+ +2] 2]/[5/[5 + +2] 2] annulation annulation through through dual dual C–H C– Rh(III)-catalyst (Scheme 30) [111]. This reaction features a [3 + 2]/[5 + 2] annulation through dual C– Hfunctionalization functionalization and and is the is firstthe straightforwardfirst straightforward procedure procedure for the synthesisfor the synthesis of the indeno[1,7- of the indeno[1,7-cd]azepine H functionalization and is the first straightforward procedure for the synthesis of the indeno[1,7- cdskeleton]azepine with skeleton good substratewith good tolerances substrate andtolerances selectivity. and selectivity. Catalystscd]azepine 2019 ,skeleton 9, x FOR PEER with REVIEW good substrate tolerances and selectivity. 14 of 28

Scheme 30. Rh(Rh(III)-catalyzedⅢ)-catalyzed synthesis of azepines.

Kim’s groupgroup in in 2017 2017 reported reported another another interesting interest Rh(III)-catalyzeding Rh(III)-catalyzed cross-coupling cross-coupling reaction betweenreaction betweenbenzylamines benzylamines and Morita-Baylis-Hillman and Morita-Baylis-Hillman (MBH) adducts (MBH) to adducts build a to wide build range a wide of 2-benzazepine range of 2- benzazepinederivatives (Scheme derivatives 31)[ (Scheme112]. This 31) [112]. transformation This transformation has a good has chemoselectivity a good chemoselectivity as well asas highwell asfunctional high functional group tolerance. group tolerance. In 2018, Chabaud and co-workers ingeniously tethered allylic alcohols into benzamide scaffold to further fulfill a Rh(III)-catalyzed aryl C–H activation/intramolecular Heck-type reaction cascade to access tricyclic azepinones through an intramolecular process (Scheme 32) [113].

Scheme 31. The synthesis of 2-benzazepines.

Scheme 32. Rh(III)-catalyzed intramolecular process to form azepinone derivatives.

5. Construction of spiroheterocycles Spiro compounds also play a vital role in life sciences and materials related fields due to their unique structural properties, which have been found broadly in natural products [114,115], pharmaceuticals [116], optoelectronics [117]. Furthermore, spirocyclic skeletons are also basic backbones for many useful and commercially available catalysts and ligands [118,119]. They could not only present central chirality but also exhibit axial chirality which depends on their substituents. However, the construction of spiro compounds has been a challenging task for synthetic chemists due to poor functional group compatibility and the difficulty to introduce versatile functionality to the parent one for further practical transformation. The traditional methods for the formation of spirocyclic molecules mainly embody alkylation process, ring-closing of compounds with geminal substituents, tandem annulation involved radical, rearrangement-based methods, ring-opening of bridged ring systems accompanied by bond-cleavage [120–122]. Recently, emerging transition-metal mediated C–H bond activation provides another convenient way to give access to spirocyclic compounds, in which several groups have reported a

Catalysts 2019, 9, x FOR PEER REVIEW 14 of 28

Scheme 30. Rh(Ⅲ)-catalyzed synthesis of azepines.

Kim’s group in 2017 reported another interesting Rh(III)-catalyzed cross-coupling reaction between benzylamines and Morita-Baylis-Hillman (MBH) adducts to build a wide range of 2- Scheme 30. Rh(Ⅲ)-catalyzed synthesis of azepines. benzazepine derivatives (Scheme 31) [112]. This transformation has a good chemoselectivity as well as high functional group tolerance. Kim’s group in 2017 reported another interesting Rh(III)-catalyzed cross-coupling reaction In 2018, Chabaud and co-workers ingeniously tethered allylic alcohols into benzamide scaffold between benzylamines and Morita-Baylis-Hillman (MBH) adducts to build a wide range of 2- to further fulfill a Rh(III)-catalyzed aryl C–H activation/intramolecular Heck-type reaction cascade to Catalystsbenzazepine2019, 9 ,derivatives 823 (Scheme 31) [112]. This transformation has a good chemoselectivity as15 well of 29 access tricyclic azepinones through an intramolecular process (Scheme 32) [113]. as high functional group tolerance. In 2018, Chabaud and co-workers ingeniously tethered allylic alcohols into benzamide scaffold to further fulfill a Rh(III)-catalyzed aryl C–H activation/intramolecular Heck-type reaction cascade to access tricyclic azepinones through an intramolecular process (Scheme 32) [113].

SchemeScheme 31.31. The synthesis of 2-benzazepines.

In 2018, Chabaud and co-workers ingeniously tethered allylic alcohols into benzamide scaﬀold to further fulﬁll a Rh(III)-catalyzed aryl C–H activation/intramolecular Heck-type reaction cascade to access tricyclic azepinones throughScheme an 31. intramolecular The synthesis of process 2-benzazepines. (Scheme 32)[113].

Scheme 32. Rh(III)-catalyzed intramolecular process to form azepinone derivatives.

5. Construction of spiroheterocycles Scheme 32. Rh(III)-catalyzed intramolecular process to form azepinone derivatives. Spiro compoundsScheme 32. Rh(III)-catalyzedalso play a vital intramolecular role in life sciences process toand form materials azepinone related derivatives. fields due to their 5.unique Construction structural of Spiroheterocyclesproperties, which have been found broadly in natural products [114,115], 5.pharmaceuticals Construction of [116], spiroheterocycles optoelectronics [117]. Furthermore, spirocyclic skeletons are also basic backbonesSpiro compoundsfor many useful also and play commercially a vital role inavailable life sciences catalysts and and materials ligands related[118,119]. fields They due could to Spiro compounds also play a vital role in life sciences and materials related fields due to their theirnot only unique present structural central properties,chirality but which also exhibit have beenaxial foundchirality broadly which independs natural on products their substituents. [114,115], unique structural properties, which have been found broadly in natural products [114,115], pharmaceuticalsHowever, the construction [116], optoelectronics of spiro compounds [117]. Furthermore, has been spirocyclic a challenging skeletons task are for also synthetic basic backbones chemists pharmaceuticals [116], optoelectronics [117]. Furthermore, spirocyclic skeletons are also basic fordue many to poor useful functional and commercially group compatibility available and catalysts the difficulty and ligands to introduce [118,119 versatile]. They functionality could not only to backbones for many useful and commercially available catalysts and ligands [118,119]. They could presentthe parent central one chiralityfor further but practical also exhibit transformation. axial chirality which depends on their substituents. However, not only present central chirality but also exhibit axial chirality which depends on their substituents. the constructionThe traditional of spiro methods compounds for the hasformation been a of challenging spirocyclic task molecules for synthetic mainly chemists embody due alkylation to poor However, the construction of spiro compounds has been a challenging task for synthetic chemists functionalprocess, ring-closing group compatibility of compounds and the with diffi geminalculty to su introducebstituents, versatile tandem functionality annulation toinvolved the parent radical, one due to poor functional group compatibility and the difficulty to introduce versatile functionality to forrearrangement-based further practical transformation. methods, ring-opening of bridged ring systems accompanied by bond-cleavage the parent one for further practical transformation. [120–122].The traditional Recently, methodsemerging for transition-metal the formation ofmediated spirocyclic C–H molecules bond activation mainly embody provides alkylation another The traditional methods for the formation of spirocyclic molecules mainly embody alkylation process,convenient ring-closing way to give of access compounds to spirocyclic with geminalcompounds, substituents, in which several tandem groups annulation have reported involved a process,radical, ring-closing rearrangement-based of compounds methods, with geminal ring-opening substituents, of bridged tandem ring annulation systems accompaniedinvolved radical, by rearrangement-basedbond-cleavage [120–122 methods,]. Recently, ring-opening emerging transition-metalof bridged ring systems mediated accompanied C–H bond activation by bond-cleavage provides [120–122]. Recently, emerging transition-metal mediated C–H bond activation provides another another convenient way to give access to spirocyclic compounds, in which several groups have reported convenienta number of way highly to give stereoselective access to spirocyclic approaches compounds, to build sophisticated in which several scaffolds groupsvia a tandem have reported sequence a with different chiral catalysts [123–125]. Cyclopropane, the smallest cycle, with poses larger inherent tension leads to the synthesis of spirocyclic molecules with a three-member ring is a very challenging task. In 2013, Cui and co-workers developed a Rh(III)-catalyzed C–H bond activation/cycloaddition of benzamides and methylene cyclopropanes to selectively synthesize spiro-dihydroisoquinolinones and furan-fused azepinones (Scheme 33)[121], which can be conducted to privileged tetrahydroisoquinoline and azepine molecules. The transformation features simple starting materials, mild conditions, high efficiency and without external oxidant. Catalysts 2019, 9, x FOR PEER REVIEW 15 of 28 number of highly stereoselective approaches to build sophisticated scaffolds via a tandem sequence with different chiral catalysts [123–125]. Cyclopropane, the smallest cycle, with poses larger inherent tension leads to the synthesis of spirocyclic molecules with a three-member ring is a very challenging task. In 2013, Cui and co- workers developed a Rh(III)-catalyzed C–H bond activation/cycloaddition of benzamides and methylene cyclopropanes to selectively synthesize spiro-dihydroisoquinolinones and furan-fused azepinonesCatalysts 2019, 9(Scheme, x FOR PEER 33) REVIEW [121], which can be conducted to privileged tetrahydroisoquinoline15 ofand 28 azepine molecules. The transformation features simple starting materials, mild conditions, high number of highly stereoselective approaches to build sophisticated scaffolds via a tandem sequence efficiency and without external oxidant. with different chiral catalysts [123–125]. Interestingly, Glorious’s group discovered an unprecedented dearomatized spirocyclopropane Cyclopropane, the smallest cycle, with poses larger inherent tension leads to the synthesis of in a sequential Rh(III)-catalyzed C–H activation and rearrangement reaction to spirocyclopropanes spirocyclic molecules with a three-member ring is a very challenging task. In 2013, Cui and co- in 2018 (Scheme 34) [122]. This protocol used N-phenoxyacetamide with a redox-natural directing workers developed a Rh(III)-catalyzed C–H bond activation/cycloaddition of benzamides and group as the C–H bond activation substrate to couple with 7-azabenzonorbornadiene, and an methylene cyclopropanes to selectively synthesize spiro-dihydroisoquinolinones and furan-fused unprecedented dearomatized spirocyclopropane intermediate was obtained in a sequential Rh(III)- azepinones (Scheme 33) [121], which can be conducted to privileged tetrahydroisoquinoline and catalyzed C−H bond activation and Wagner–Meerwein-type rearrangement reaction, in which the N- azepine molecules. The transformation features simple starting materials, mild conditions, high phenoxyacetamides acted as a one-carbon component in this [1 + 2] annulation. efficiency and without external oxidant. Recently, the transition-metal mediated dearomatization reactions have drawn great attentions Interestingly, Glorious’s group discovered an unprecedented dearomatized spirocyclopropane due to the fact that such transformation can convert planar 2D aromatic molecules into very complex in a sequential Rh(III)-catalyzed C–H activation and rearrangement reaction to spirocyclopropanes and more flexible 3D compounds with various fused and spiro polycyclic motifs [126,127]. Among in 2018 (Scheme 34) [122]. This protocol used N-phenoxyacetamide with a redox-natural directing these achievements, substrates with a phenol framework have received considerable attention group as the C–H bond activation substrate to couple with 7-azabenzonorbornadiene, and an because the hydroxyl group can not only serve as a directing group to spur C–H bond cleavage, but unprecedented dearomatized spirocyclopropane intermediate was obtained in a sequential Rh(III)- also facilitate dearomatization of planar aromatic feedstocks. In 2014, Gulías and coworkers described catalyzed C−H bond activation and Wagner–Meerwein-type rearrangement reaction, in which the N- a novel [3 + 2] cycloaddition between 2-alkenylphenols and alkynes by Rh(III)-catalyzed under phenoxyacetamides acted as a one-carbon component in this [1 + 2] annulation. oxidative conditions to give a novel spirocarbocycles (Scheme 35) [120]. Further, Lam’s group also Recently, the transition-metal mediated dearomatization reactions have drawn great attentions developed a catalytic C–H functionalization method for the dearomatizing spiroannulation of 2- due to the fact that such transformation can convert planar 2D aromatic molecules into very complex alkenylphenols with alkynes and enynes (Scheme 35) [128]. Their results pointed out the potential of Catalystsand more2019 flexible, 9, 823 3D compounds with various fused and spiro polycyclic motifs [126,127]. Among16 of 29 using substituents in key strategic positions of substrates to change reaction outcomes. these achievements, substrates with a phenol framework have received considerable attention because the hydroxyl group can not only serve as a directing group to spur C–H bond cleavage, but also facilitate dearomatization of planar aromatic feedstocks. In 2014, Gulías and coworkers described a novel [3 + 2] cycloaddition between 2-alkenylphenols and alkynes by Rh(III)-catalyzed under oxidative conditions to give a novel spirocarbocycles (Scheme 35) [120]. Further, Lam’s group also developed a catalytic C–H functionalization method for the dearomatizing spiroannulation of 2- alkenylphenols with alkynes and enynes (Scheme 35) [128]. Their results pointed out the potential of using substituents in key strategic positions of substrates to change reaction outcomes.

Scheme 33. TheThe synthesis synthesis of of spiro-2 spiro-2H-isoquinolinones-isoquinolinones and and fu furan-fusedran-fused azepinones.

Interestingly, Glorious’s group discovered an unprecedented dearomatized spirocyclopropane in a sequential Rh(III)-catalyzed C–H activation and rearrangement reaction to spirocyclopropanes in 2018 (Scheme 34)[122]. This protocol used N-phenoxyacetamide with a redox-natural directing group as the C–H bond activation substrate to couple with 7-azabenzonorbornadiene, and an unprecedented dearomatized spirocyclopropane intermediate was obtained in a sequential Rh(III)-catalyzed C H bond − activation and Wagner–Meerwein-typeScheme 34. The synthesis rearrangement of the dearomatized reaction, spirocyclopropane. in which the N-phenoxyacetamides acted as a one-carbonScheme 33. component The synthesis in of this spiro-2 [1 +H2]-isoquinolinones annulation. and furan-fused azepinones.

Scheme 34. The synthesis of the dearomatized spirocyclopropane. Scheme 34. The synthesis of the dearomatized spirocyclopropane. Recently, the transition-metal mediated dearomatization reactions have drawn great attentions due to the fact that such transformation can convert planar 2D aromatic molecules into very complex and more ﬂexible 3D compounds with various fused and spiro polycyclic motifs [126,127]. Among these achievements, substrates with a phenol framework have received considerable attention because the hydroxyl group can not only serve as a directing group to spur C–H bond cleavage, but also facilitate dearomatization of planar aromatic feedstocks. In 2014, Gulías and coworkers described a novel [3 + 2] cycloaddition between 2-alkenylphenols and alkynes by Rh(III)-catalyzed under oxidative conditions to give a novel spirocarbocycles (Scheme 35)[120]. Further, Lam’s group also developed a catalytic C–H functionalization method for the dearomatizing spiroannulation of 2-alkenylphenols with alkynes and enynes (Scheme 35)[128]. Their results pointed out the potential of using substituents in key strategicCatalysts 2019 positions, 9, x FOR PEER of substratesREVIEW to change reaction outcomes. 16 of 28

SchemeScheme 35. Rh 35. (III)-catalyzed Rh (III)-catalyzed dearomatizing dearomatizing [3 [3 ++ 2]2] annulation annulation of 2-alkenylphenols. of 2-alkenylphenols.

Scheme 36. Rh(III)-catalyzed asymmetric dearomatization of naphthols.

Catalysts 2019, 9, 823 17 of 29

YouCatalysts and 2019 co-workers, 9, x FOR PEER are REVIEW committed to developing synthetic methodologies that involve16 of mainly28 transition-metal catalyzed stereoselectively C–H bond functionalization and catalytic asymmetric dearomatizaton reactions [127]. In 2015, they developed an Rh(III)-catalyzed enantioselective dearomatization of 1-aryl-2-naphthols with internal alkynes via C H functionalization reaction [129,130] − by utilizing the Rh/chiral cyclopentadienyl (Cp) catalyst developed by the Cramer group which shows preeminent activity in promoting asymmetric C H activation (Scheme 36) [118,131,132]. This process − can afford spirocyclic compounds with high yields and excellent ee value. They also proposed a possible mechanism for the reaction. With the deprotonation of the β-naphthol substrates by the Rh catalyst, the catalytic cycle begins. The obtained intermediate I then undergoes C H bond activation, which leads − to the rhodacycle II. Rhodacycle III involves alkyne coordination and migratory insertion and gives a rather strained eight-membered isomer, which might be in equilibrium with a six-member isomer IV. After reductive elimination, the final dearomatized product is obtained, and the released Rh(I) species is concomitantly oxidized by Cu(OAc)2 and oxygen to the activated Rh(III) catalyst, completing the catalytic cycle. Scheme 35. Rh (III)-catalyzed dearomatizing [3 + 2] annulation of 2-alkenylphenols.

SchemeScheme 36. 36.Rh(III)-catalyzed Rh(III)-catalyzed asymmetricasymmetric dearomatization dearomatization of naphthols. of naphthols.

Catalysts 2019, 9, x FOR PEER REVIEW 17 of 28 Catalysts 2019, 9, x FOR PEER REVIEW 17 of 28

You and co-workers are committed to developing synthetic methodologies that involve mainly transition-metal catalyzed stereoselectively C–H bond functionalization and catalytic asymmetric dearomatizaton reactions [127]. In 2015, they developed an Rh(III)-catalyzed enantioselective dearomatization of 1-aryl-2-naphthols with internal alkynes via C−H functionalization reaction [129,130] by utilizing the Rh/chiral cyclopentadienyl (Cp) catalyst developed by the Cramer group which shows preeminent activity in promoting asymmetric C−H activation (Scheme 36) [118,131,132]. This process can afford spirocyclic compounds with high yields and excellent ee value. They also proposed a possible mechanism for the reaction. With the deprotonation of the β-naphthol substrates by the Rh catalyst, the catalytic cycle begins. The obtained intermediate I then undergoes C−H bond activation, which leads to the rhodacycle II. Rhodacycle III involves alkyne coordination and migratory insertion and gives a rather strained eight-membered isomer, which might be in equilibrium with a six-member isomer IV. After reductive elimination, the final dearomatized product is obtained, and the released Rh(I) species is concomitantly oxidized by Cu(OAc)2 and productCatalysts 2019 is , obtained,9, 823 and the released Rh(I) species is concomitantly oxidized by Cu(OAc)182 and of 29 oxygen to the activated Rh(III) catalyst, completing the catalytic cycle. Similar to phenol skeletons, pyrazolones also are utilized for the synthesis of novel structurally spirocyclic molecules. In 2017, Yao’s group developed an Rh(III)-catalyzed enol-directed formal sp3 spirocyclicSimilar molecules. to phenol In skeletons, 2017, Yao’s pyrazolones group deve alsoloped are utilized an Rh(III)-catalyzed for the synthesis enol-directed of novel structurally formal sp3 Cspirocyclic−H bond molecules. activation In 2017,and Yao’sannulation group developedof α-arylidene an Rh(III)-catalyzed pyrazolones enol-directedwith alkynes formal to spprovide3 C H − spiropentadienebond activation andpyrazolones annulation with of α-arylidene broadly pyrazolonesbiological activity with alkynes [133] toin providegood yields spiropentadiene at room temperaturepyrazolones with(Scheme broadly 37) biological[134]. activity [133] in good yields at room temperature (Scheme 37)[134].

Scheme 37. The synthesis of spiropentadiene pyrazolones. Scheme 37. TheThe synthesis synthesis of spiropentadiene pyrazolones.

In the same year, You’s groupgroup developeddeveloped a asymmetric synthesis of ﬁve-member-ringfive-member-ring spiropyrazolones from from readily available pyrazolones and and alkynes though a chiral ( S)-Cp*Rh(III) catalyzed C–H functionalizationfunctionalization/annulation/annulation proce processss (Scheme 38)38)[ [135].135]. This This reaction tolerated the transformation of a wide range of substrates into highly enantioenriched spiropyrazolones.spiropyrazolones.

Scheme 38. The enantioselective synthesis of spiroindenes. Scheme 38. The enantioselective synthesis of spiroindenes. Scheme 38. The enantioselective synthesis of spiroindenes. The 1,3-dicarbonyl compounds are the excellent precursor for enol, where two carbonyl The 1,3-dicarbonyl compounds are the excellent precursor for enol, where two carbonyl groups groupsThe increase 1,3-dicarbonyl the acidity compounds of dual arαe-H the which excellent leads precursor to the factfor enol, that where 1,3-dicarbonyl two carbonyl compounds groups increase the acidity of dual α-H which leads to the fact that 1,3-dicarbonyl compounds can convert increasecan convert the intoacidity enol of easily. dual Inα-H 2015, which Lam leads and co-workersto the fact that described 1,3-dicarbonyl an Rh(III)-catalyzed compounds annulation can convert of into enol easily. In 2015, Lam and co-workers described an Rh(III)-catalyzed annulation of 5- into5-arylbarbituric enol easily. acids In 2015, and relatedLam and compounds co-workers with described 1,3-enynes an containing Rh(III)-catalyzed allylic hydrogens annulation cis toof the5- arylbarbituric acids and related compounds with 1,3-enynes containing allylic hydrogens cis to the arylbarbituricalkyne (Scheme acids 39)[ and136 ].related This novel compounds mode of with oxidative 1,3-enynes annulation containing further allylic demonstrates hydrogens the cis powerto the alkyne (Scheme 39) [136]. This novel mode of oxidative annulation further demonstrates the power alkyneof alkenyl-to-allyl (Scheme 39) 1,4-Rhodium(III) [136]. This novel migration mode of inoxidative generating annulation electrophilic further allylrhodium demonstrates species the power in the of alkenyl-to-allyl 1,4-Rhodium(III) migration in generating electrophilic allylrhodium species in the ofCatalystsconstruction alkenyl-to-allyl 2019, 9,of x FOR polycyclic 1,4-Rhodium(III) PEER REVIEW systems. migration in generating electrophilic allylrhodium species18 in of the 28 construction of polycyclic systems.

Scheme 39. Rh(III)-catalyzedRh(III)-catalyzed synthesis synthesis of polycyclic scaffold. scaﬀold.

Also, in 2015, by using chiral cyclopentadienylcyclopentadienyl Rhodium catalysts, Lam developed an enantioselective synthesissynthesis of of spiroindenes spiroindenes from from the oxidativethe oxidative annulation annulation of an aryl of cyclican aryl 1,3-dicarbonyl cyclic 1,3- dicarbonylcompounds compounds (or their enol (or tautomers)their enol tautomers) with alkynes with (Scheme alkynes 40(Sch)[137eme]. 40) The [137]. process The couldprocess apply could a wideapply range a wide of range substrates of substrates to give diverse to give productsdiverse products with high with enantioselectivities. high enantioselectivities. A proposed A proposed catalytic catalyticcycle for cycle these for reactions these reactions is shown is shown in Scheme in Sche 41.me The 41. author The author proposed proposed a mechanism a mechanism to explain to explain the thesource source of reaction of reaction stereoselectivity. stereoselectivity. It can It can be seenbe seen from from the diagramthe diagram of reaction of reaction mechanism mechanism that that the theunique unique conﬁguration configuration and stericand ster hindranceic hindrance of ligand of ligand formation formation playan play important an important role in role the controlin the controlof stereoselectivity. of stereoselectivity.

Scheme 40. The asymmetric synthesis of five-member-ring spiropyrazolones.

In 2014, Li and coworkers employed 1H-pyrroles as a substrate of C–H activation to finish a Rhodium(III)catalyzed [3 + 2] annulation with internal alkynes via aryl C(sp2)-H/alkene functionalization where the N-atom of enamine as a directing group (Scheme 42) [138]. This novel reaction was a general method for the construction of the spiro [indene-1,2’-pyrrolidine] ring system, which offered excellent functional group tolerances and excellent selectivity. Functionalized sulfonamides such as sultams and sulfamidates are important intermediates to synthesize diverse biologically active molecules [139]. In 2013, Deng conducted an efficient Rh(III)- catalyzed [3 + 2] annulation of cyclic N-sulfonyl ketimines with internal alkynes proceeded by catalytic amounts of AgSbF6 to form synthetically fused spirocyclic sultams (Scheme 43) [140]. This reaction features high yield and mild conditions. In 2014, Dong developed another novel Rh(III)- catalyzed three-component reaction of imines, alkynes, and aldehydes via C–H activation (Scheme 44) [141]. This reaction afforded a method for the construction of polycyclic skeletons and allowed the formation of four new bonds in a simple-to-perform, single-operation cascade C–H bond activation/C=N insertion, C–H bond activation/C=O insertion, cyclization sequence.

Catalysts 2019, 9, x FOR PEER REVIEW 18 of 28

Scheme 39. Rh(III)-catalyzed synthesis of polycyclic scaffold.

Also, in 2015, by using chiral cyclopentadienyl Rhodium catalysts, Lam developed an enantioselective synthesis of spiroindenes from the oxidative annulation of an aryl cyclic 1,3- dicarbonyl compounds (or their enol tautomers) with alkynes (Scheme 40) [137]. The process could apply a wide range of substrates to give diverse products with high enantioselectivities. A proposed catalytic cycle for these reactions is shown in Scheme 41. The author proposed a mechanism to explain the source of reaction stereoselectivity. It can be seen from the diagram of reaction mechanism that Catalysts 2019, 9, 823 19 of 29 the unique configuration and steric hindrance of ligand formation play an important role in the control of stereoselectivity.

Catalysts 2019, 9, x FOR PEER REVIEW 19 of 28 Scheme 40. The asymmetric synthesis of ﬁve-member-ring spiropyrazolones. Scheme 40. The asymmetric synthesis of five-member-ring spiropyrazolones.

In 2014, Li and coworkers employed 1H-pyrroles as a substrate of C–H activation to finish a Rhodium(III)catalyzed [3 + 2] annulation with internal alkynes via aryl C(sp2)-H/alkene functionalization where the N-atom of enamine as a directing group (Scheme 42) [138]. This novel Catalysts 2019, 9, x FOR PEER REVIEW 19 of 28 reaction was a general method for the construction of the spiro [indene-1,2’-pyrrolidine] ring system, which offered excellent functional group tolerances and excellent selectivity. Functionalized sulfonamides such as sultams and sulfamidates are important intermediates to synthesize diverse biologically active molecules [139]. In 2013, Deng conducted an efficient Rh(III)- catalyzed [3 + 2] annulation of cyclic N-sulfonyl ketimines with internal alkynes proceeded by catalytic amounts of AgSbF6 to form synthetically fused spirocyclic sultams (Scheme 43) [140]. This reaction features high yield and mild conditions. In 2014, Dong developed another novel Rh(III)- catalyzed three-component reaction of imines, alkynes, and aldehydes via C–H activation (Scheme 44) [141]. This reaction afforded a method for the construction of polycyclic skeletons and allowed the formation of four new bonds in a simple-to-perform, single-operation cascade C–H bond activation/C=N insertion, C–H bond activation/C=O insertion, cyclization sequence.

SchemeScheme 41. AA proposed proposed catalytic catalytic cycle cycle of of the the asymmetric asymmetric synthesis. synthesis.

Scheme 42. The synthesis of the spiro [indene-1,2’-pyrrolidine] ring system.

SchemeScheme 42. 42. TheThe synthesis synthesis of of the the spiro spiro [indene-1,2’-pyrrolidine] ring system.

Functionalized sulfonamides such as sultams and sulfamidates are important intermediates to synthesize diverse biologically active molecules [139]. In 2013, Deng conducted an eﬃcient Rh(III)-catalyzed [3 + 2] annulation of cyclic N-sulfonyl ketimines with internal alkynes proceeded Scheme 43. Rh(III)-catalyzed [3 + 2] annulation via N-Rh-O species. by catalytic amounts of AgSbF6 to form synthetically fused spirocyclic sultams (Scheme 43)[140]. This reaction features high yield and mild conditions. In 2014, Dong developed another novel

Scheme 43. Rh(III)-catalyzed [3 + 2] annulation via N-Rh-O species.

Scheme 44. Rh(III)-catalyzed three-component reaction.

Catalysts 2019, 9, x FOR PEER REVIEW 19 of 28 Catalysts 2019, 9, x FOR PEER REVIEW 19 of 28

Scheme 41. A proposed catalytic cycle of the asymmetric synthesis. Scheme 41. A proposed catalytic cycle of the asymmetric synthesis.

Catalysts 2019, 9, 823 20 of 29

Rh(III)-catalyzed three-component reaction of imines, alkynes, and aldehydes via C–H activation

(Scheme 44)[141]. This reaction aﬀorded a method for the construction of polycyclic skeletons and allowed the formationScheme of 42. four The new synthesis bonds of inthe a spiro simple-to-perform, [indene-1,2’-pyrrolidine] single-operation ring system. cascade C–H bond activation/C=NScheme insertion, 42. C–HThe synthesis bond activation of the spiro/C= [indene-1,2’-pyrrolidine]O insertion, cyclization ring sequence. system.

Scheme 43. Rh(III)-catalyzed [3 + 2] annulation via N-Rh-O species. Scheme 43. Rh(III)-catalyzed [3 + 2]2] annulation annulation viavia N-Rh-ON-Rh-O species. species.

Catalysts 2019,, 9,, xx FORFOR PEERPEER REVIEWREVIEWScheme 44. Rh(III)-catalyzed three-component reaction. 20 of 28 Scheme 44. Rh(III)-catalyzed three-component reaction. Similarly, olefins oleﬁns can can also also undergo undergo [3 [3 + 2]+ cycloaddition2] cycloaddition with with cyclic cyclic N-sulfonylN-sulfonyl ketimine. ketimine. In 2017, In Li2017, realized Li realized Rh(III)-catalyzed Rh(III)-catalyzed [3 + 2] annulation [3 + 2] annulation of cyclic ofN-sulfonyl cyclic N-sulfonyl or N-acyl or ketiminesN-acyl ketimines with activated with activated alkenes, which led to the synthesis of spirocycles with three continuous stereogenic centers alkenes, which led to the synthesis of spirocycles with three continuous stereogenic centers (Scheme 45)(Scheme [142]. 45 This)[142 reaction]. This reactionproceeded proceeded as highly as ef highlyficient e ﬃundercient mild under and mild redox-neutral and redox-neutral conditions conditions via aa Cvia−Ha CbondH bond activation activation pathway, pathway, and and the thecoupling coupling is diastereodivergent, is diastereodivergent, with with the the diastereoselectivity diastereoselectivity C−H bond− activation pathway, and the coupling is diastereodivergent, with the diastereoselectivity being tuned by silver additives.

Scheme 45.45. Rh(III)-catalyzed [3 + 2]2] annulation annulation for for synthesizing synthesizing spirocycles. spirocycles.

Moreover, electron-richelectron-rich aromatic compounds are also suitablesuitable couplingcoupling partnerspartners ofof thisthis this protocol.protocol. protocol. In 2016, Wei Wei developed a Rh(III)-c Rh(III)-catalyzedatalyzed cross dehydrogenative co couplingupling method to obtain various structurally interesting and synthetically useful spirocyclic sultams and heterobiaryls from readily available N-sulfonylketimines-sulfonylketimines and and thiophenes thiophenes or furans (Scheme 46)46)[ [143],143], thethe NN-sulfonylimine-sulfonylimine functionality was employed asas anan eeﬀectiveective directingdirecting groupgroup forfor CC−H bond activation. −

Scheme 46. Rh(III)-catalyzedRh(III)-catalyzed synthesis of spirocyclic sultams.

Although chiral sultams play an important role in organic and medicinal chemistry [144, 145], only a few methods for the synthesis of chiral sultams have been reported. Until 2016, Cramer reported a chiral Cpx-Rhodium(III) catalyzed synthesis of spirocyclic indenyl sultams by enantioselective annulation of N-sulfonyl ketimines and alkynes (Scheme 47) [146]. This reaction could obtain spirocyclic sultams in high yields and enantiomeric ratios. Moreover, this study further illustratedillustrated thethe generalitygenerality ofof thethe chiralchiral cyclopentadienylscyclopentadienyls basedbased onon anan atropchiralatropchiral biarylbiaryl backbonebackbone asas a versatile chiral ligand class.

Scheme 47. Chiral Rh(III)-catalyzed synthesis of spirocyclic indenyl sultams.

Cyclic imines are of prime importance as they could lead to the formation of spirocompounds via aa [3[3 ++ 2]2] annulationannulation reaction.reaction. InIn 2016,2016, KimKim describeddescribed TheThe Rh(III)-catalyzedRh(III)-catalyzed redox-neutralredox-neutral couplingcoupling process of N-acyl ketimines generated inin situsitu fromfrom 3-hydroxyisoindolinones3-hydroxyisoindolinones withwith aa widewide rangerange ofof activated olefins (Scheme 48) [147]. This approach led to the synthesis of bioactive spiroisoindolinone derivatives in good yields. Spiroindanes were obtained by the [3 + 2] annulations reaction in the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates. Notably, acrylates and quinones displayed the β-H elimination followed by Prins-type cyclization furnishing spiroindenes.

Catalysts 2019, 9, x FOR PEER REVIEW 20 of 28

Similarly, olefins can also undergo [3 + 2] cycloaddition with cyclic N-sulfonyl ketimine. In 2017, Li realized Rh(III)-catalyzed [3 + 2] annulation of cyclic N-sulfonyl or N-acyl ketimines with activated alkenes, which led to the synthesis of spirocycles with three continuous stereogenic centers (Scheme 45) [142]. This reaction proceeded as highly efficient under mild and redox-neutral conditions via a C−H bond activation pathway, and the coupling is diastereodivergent, with the diastereoselectivity being tuned by silver additives.

Scheme 45. Rh(III)-catalyzed [3 + 2] annulation for synthesizing spirocycles.

Moreover, electron-rich aromatic compounds are also suitable coupling partners of this protocol. In 2016, Wei developed a Rh(III)-catalyzed cross dehydrogenative coupling method to obtain various structurally interesting and synthetically useful spirocyclic sultams and heterobiaryls from readily available N-sulfonylketimines and thiophenes or furans (Scheme 46) [143], the N-sulfonylimine functionality was employed as an eﬀective directing group for C−H bond activation.

Scheme 46. Rh(III)-catalyzed synthesis of spirocyclic sultams. Catalysts 2019, 9, 823 21 of 29

Although chiral sultams play an important role in organic and medicinal chemistry [144, 145], only Althougha few methods chiral sultams for the play synthesis an important of chiral role sultams in organic have and medicinalbeen reported. chemistry Until [144 2016,,145 ],Cramer only a fewreported methods a forchiral the synthesisCpx-Rhodium( of chiralIII) sultams catalyzed have beensynthe reported.sis of Untilspirocyclic 2016, Cramer indenyl reported sultams a chiral by Cpx-Rhodium(III)enantioselective annulation catalyzed synthesisof N-sulfonyl of spirocyclic ketimines indenyl and alkynes sultams (Scheme by enantioselective 47) [146]. annulationThis reaction of Ncould-sulfonyl obtain ketimines spirocyclic and sultams alkynes in (Scheme high yields 47)[ an146d]. enantiomeric This reaction ratios. could Moreover, obtain spirocyclic this study sultams further in highillustrated yields the and generality enantiomeric of the ratios. chiral Moreover, cyclopentadienyls this study furtherbased on illustrated an atropchiral the generality biaryl backbone of the chiral as cyclopentadienylsa versatile chiral ligand based class. on an atropchiral biaryl backbone as a versatile chiral ligand class.

Scheme 47. Chiral Rh(III)-catalyzed synthesis of spirocyclic indenyl sultams.

Cyclic iminesimines areare ofof prime prime importance importance as as they they could could lead lead to to the the formation formation of spirocompoundsof spirocompoundsvia avia [3 a+ [32] + annulation2] annulation reaction. reaction. In In 2016, 2016, Kim Kim described described The The Rh(III)-catalyzed Rh(III)-catalyzed redox-neutralredox-neutral couplingcoupling processprocess ofof NN-acyl-acyl ketiminesketimines generatedgenerated inin situsitu fromfrom 3-hydroxyisoindolinones3-hydroxyisoindolinones with a widewide rangerange ofof activated oleﬁnsolefins (Scheme(Scheme 4848))[ [147].147]. This approach led to the synthesis of bioactive spiroisoindolinone derivatives inin goodgood yields.yields. Spiroindanes werewere obtainedobtained byby thethe [3[3 ++ 2] annulations reaction in the case of internal oleﬁnsolefins suchsuch asas maleimides,maleimides, maleates,maleates, fumarates,fumarates, andand cinnamates.cinnamates. Notably, acrylatesacrylates andand Catalysts 2019, 9, x FOR PEER REVIEW 21 of 28 quinonesCatalysts 2019 displayeddisplayed, 9, x FOR PEER thethe ββREVIEW-H-H eliminationelimination followedfollowed byby Prins-typePrins-type cyclizationcyclization furnishingfurnishing spiroindenes.spiroindenes.21 of 28

Scheme 48. Rh(III)-catalyzed synthesis of spiroisoindolinone derivatives. Scheme 48. Rh(III)-catalyzed synthesis of spiroisoindolinone derivatives. Additionally, in 2016, Liu’s group took advantage of the ring-opening ability of 7- Additionally, in 2016, 2016, Liu’s Liu’s group group took took ad advantagevantage of ofthe the ring-opening ring-opening ability ability of of7- oxabenzonorbornadiene to develop a new cascade reaction of alkynols and 7- 7-oxabenzonorbornadieneoxabenzonorbornadiene toto develop develop a new cascadea new reaction cascade of alkynols reaction and 7-oxabenzonorbornadienesof alkynols and 7- oxabenzonorbornadienes by synergistic Rh(III)/Sc(III) catalysis (Scheme 49) [148]. The process byoxabenzonorbornadienes synergistic Rh(III)/Sc(III) by catalysissynergistic (Scheme Rh(III)/S 49c(III)) [148 catalysis]. The (Schem processe involves49) [148]. intramolecular The process involves intramolecular addition of the hydration product of alkynols, hemiketal-directed C−H bond additioninvolves ofintramolecular the hydration addition product of of the alkynols, hydration hemiketal-directed product of alkynols, C H hemiketal-directed bond activation, followed C−H bond by activation, followed by dehydrative naphthylation and Prins-type− cyclizationation, which could dehydrativeactivation, followed naphthylation by dehydrative and Prins-type naphthylation cyclizationation, and which Prins-type could obtaincyclizationation, spirocyclic dihydrobenzowhich could obtain spirocyclic dihydrobenzo [a]-fluorenefurans with excellent regioselectivity and good yield. [obtaina]-fluorenefurans spirocyclic withdihydrobenzo excellent regioselectivity [a]-fluorenefurans and good with yield.excellent regioselectivity and good yield.

SchemeScheme 49. SynergisticSynergistic Rh(III)/Sc(I Rh(III)/Sc(III)-catalyticII)-catalytic system. Scheme 49. Synergistic Rh(III)/Sc(III)-catalytic system. Last year, Luo’s team developed a [3 + 2] annulation reaction of aromatic imine substrates and Last year, Luo’s team developed a [3 + 2] annulation reaction of aromatic imine substrates and maleimidesLast year,via Luo’sRh(III)-catalyzed team developed C H a bond[3 + 2] activation annulation strategy reaction (Scheme of aromatic 50)[149 imine]. This substrates protocol and is maleimides via Rh(III)-catalyzed C−H bond activation strategy (Scheme 50) [149]. This protocol is applicablemaleimides to via a broadRh(III)-catalyzed scope of imines C−H including bond activation cyclic/acyclic strategy ketimines (Scheme and 50) aldimines,[149]. This in protocol which anis applicable to a broad scope of imines including cyclic/acyclic ketimines and aldimines, in which an activationapplicable moietyto a broad such scope as an of acyl imines or a sulfonylincluding group cyclic/acyclic was not required.ketimines and aldimines, in which an activation moiety such as an acyl or a sulfonyl group was not required. activation moiety such as an acyl or a sulfonyl group was not required.

Scheme 50. A [3 + 2] annulation reaction for a fused spiroheterocycle. Scheme 50. A [3 + 2] annulation reaction for a fused spiroheterocycle. 6. Conclusion 6. Conclusion The Rhodium(III)-catalyzed C–H bond activation and subsequent tandem annulation reaction The Rhodium(III)-catalyzed C–H bond activation and subsequent tandem annulation reaction with π-component features atom- and step-economic, bench-stability, mild condition, and minimal with π-component features atom- and step-economic, bench-stability, mild condition, and minimal by-products and, in recent years, has caused attracted attention from synthetic chemists with its by-products and, in recent years, has caused attracted attention from synthetic chemists with its broad applications in the synthesis of heterocycles molecules with sp3 carbon center. However, most broad applications in the synthesis of heterocycles molecules with sp3 carbon center. However, most of these new reactions are still limited to substrates with specific directed groups which need to be of these new reactions are still limited to substrates with specific directed groups which need to be introduced before C–H bond activation and removed after, and thus greatly constrain its industrial introduced before C–H bond activation and removed after, and thus greatly constrain its industrial application, and will not be the preferred protocol for medicinal chemistry scientists. Especially the application, and will not be the preferred protocol for medicinal chemistry scientists. Especially the construction of chirality is still very difficult and insufficient. Therefore, further developments are construction of chirality is still very difficult and insufficient. Therefore, further developments are expected to be able to address these questions and realize its industrial applications. expected to be able to address these questions and realize its industrial applications. Funding: We are grateful to the National Natural Science Foundation of China (No.21672232) and the Strategic Funding: We are grateful to the National Natural Science Foundation of China (No.21672232) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040217 and XDA12020375) for financial Priority Research Program of the Chinese Academy of Sciences (XDA12040217 and XDA12020375) for financial support. support. Conflicts of Interest: The author declares no conflict of interest. Conflicts of Interest: The author declares no conflict of interest.

Catalysts 2019, 9, x FOR PEER REVIEW 21 of 28

Scheme 48. Rh(III)-catalyzed synthesis of spiroisoindolinone derivatives.

Additionally, in 2016, Liu’s group took advantage of the ring-opening ability of 7- oxabenzonorbornadiene to develop a new cascade reaction of alkynols and 7- oxabenzonorbornadienes by synergistic Rh(III)/Sc(III) catalysis (Scheme 49) [148]. The process involves intramolecular addition of the hydration product of alkynols, hemiketal-directed C−H bond activation, followed by dehydrative naphthylation and Prins-type cyclizationation, which could obtain spirocyclic dihydrobenzo [a]-fluorenefurans with excellent regioselectivity and good yield.

Scheme 49. Synergistic Rh(III)/Sc(III)-catalytic system.

Last year, Luo’s team developed a [3 + 2] annulation reaction of aromatic imine substrates and maleimides via Rh(III)-catalyzed C−H bond activation strategy (Scheme 50) [149]. This protocol is applicableCatalysts 2019 ,to9, a 823 broad scope of imines including cyclic/acyclic ketimines and aldimines, in which22 of an 29 activation moiety such as an acyl or a sulfonyl group was not required.

Scheme 50. A [3 + 2]2] annulation annulation reaction reaction for for a a fused fused spiroheterocycle. spiroheterocycle.

6. Conclusion Conclusions The Rhodium(III)-catalyzed C–H C–H bond activation and subsequent tandem annulation reaction with π-component features atom- and step-economic, bench-stability, mild condition, and minimal by-products and,and, inin recent recent years, years, has has caused caused attracted attracted attention attention from from synthetic synthetic chemists chemists with itswith broad its 3 broadapplications applications in the synthesisin the synthesis of heterocycles of heterocycles molecules molecules with sp withcarbon sp3 center.carbon However,center. However, most of thesemost ofnew these reactions new reactions are still limited are still to limited substrates to substrates with specific with directed specific groups directed which groups need which to be introducedneed to be introducedbefore C–H before bond activationC–H bond and activation removed and after, removed and thus after, greatly and thus constrain greatly its constrain industrial its application, industrial application,and will not and be the will preferred not be the protocol preferred for medicinal protocol chemistryfor medicinal scientists. chemistry Especially scientists. the constructionEspecially the of constructionchirality is still of verychirality difficult is still and very insu ffidifficultcient. Therefore,and insufficient. further Therefore, developments further are expecteddevelopments to be ableare expectedto address to these be able questions to address and these realize questions its industrial and realize applications. its industrial applications.

Funding: We areare grateful grateful to to the the National National Natural Natural Science Science Foundation Foundation of China of China (No.21672232) (No.21672232) and the and Strategic the Strategic Priority PriorityResearch Research Program Program of the Chinese of the AcademyChinese Acade of Sciencesmy of (XDA12040217 Sciences (XDA12040217 and XDA12020375) and XDA12020375) for financial for support. financial support.Conflicts of Interest: The author declares no conflict of interest. Conflicts of Interest: The author declares no conflict of interest. References

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